Substituted nucleosides, nucleotides and analogs thereof

ABSTRACT

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection, with a nucleoside, a nucleotide and an analog thereof.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified, for example, in the Application Data Sheet or Request asfiled with the present application, are hereby incorporated by referenceunder 37 CFR 1.57, and Rules 4.18 and 20.6.

REFERENCE TO SEQUENCE LISTING

The present application is filed with a Sequence Listing in Electronicformat. The Sequence Listing is provided as a file entitledALIOS076C2.txt, created Feb. 13, 2018, which is approximately 4 kb insize. The information in the electronic format of the sequence listingis incorporated herein by reference in its entirety.

BACKGROUND Field

The present application relates to the fields of chemistry, biochemistryand medicine. More particularly, disclosed herein are nucleoside,nucleotides and analogs thereof, pharmaceutical compositions thatinclude one or more nucleosides, nucleotides and analogs thereof, andmethods of synthesizing the same. Also disclosed herein are methods ofameliorating and/or treating a paramyxovirus viral infection with one ormore nucleosides, nucleotides and analogs thereof.

DESCRIPTION

Respiratory viral infections, including upper and lower respiratorytract viral infections, infects and is the leading cause of death ofmillions of people each year. Upper respiratory tract viral infectionsinvolve the nose, sinuses, pharynx and/or larynx. Lower respiratorytract viral infections involve the respiratory system below the vocalcords, including the trachea, primary bronchi and lungs.

Nucleoside analogs are a class of compounds that have been shown toexert antiviral activity both in vitro and in vivo, and thus, have beenthe subject of widespread research for the treatment of viralinfections. Nucleoside analogs are usually therapeutically inactivecompounds that are converted by host or viral enzymes to theirrespective active anti-metabolites, which, in turn, may inhibitpolymerases involved in viral or cell proliferation. The activationoccurs by a variety of mechanisms, such as the addition of one or morephosphate groups and, or in combination with, other metabolic processes.

SUMMARY

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a paramyxovirus viral infection that can includeadministering to a subject suffering from the paramyxovirus viralinfection an effective amount of one or more compounds of Formula (I),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Other embodiments describedherein relate to using one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for ameliorating and/or treating a paramyxovirus viralinfection. Still other embodiments described herein relate to compoundsof Formula (I), or a pharmaceutically acceptable salt thereof, that canbe used for ameliorating and/or treating a paramyxovirus viralinfection. Yet still other embodiments disclosed herein relate tomethods of ameliorating and/or treating a paramyxovirus viral infectionthat can include contacting a cell infected with the paramyxovirus withan effective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition that includes one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof. Some embodiments disclosedherein relate to methods of inhibiting the replication of aparamyxovirus that can include contacting a cell infection with theparamyxovirus with an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition that includes one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments disclosed herein relate to methods of amelioratingand/or treating a paramyxovirus viral infection that can includeadministering to a subject suffering from the viral infection aneffective amount of a compound described herein or a pharmaceuticallyacceptable salt thereof (for example, one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof), or a pharmaceuticalcomposition that includes one or more compounds described herein, incombination with one or more agents described herein. Some embodimentsdisclosed herein relate to methods of ameliorating and/or treating aparamyxovirus viral infection that can include contacting a cellinfected with the virus with an effective amount of a compound describedherein or a pharmaceutically acceptable salt thereof (for example, oneor more compounds of Formula (I), or a pharmaceutically acceptable saltthereof), or a pharmaceutical composition that includes one or morecompounds described herein, in combination with one or more agentsdescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows example anti-RSV agents.

DETAILED DESCRIPTION

Paramyxoviridae family is a family of single stranded RNA viruses.Several genera of the paramyxoviridae family include respirovirus,rubulavirus, pneumovirus and metapneumovirus. These viruses can betransmitted person to person via direct or close contact withcontaminated respiratory droplets or fomites.

Human Respiratory Syncytial Virus (RSV) is a species of pneumovirus anda negative single-stranded RNA virus. RSV can cause respiratoryinfections, and can be associated with bronchiolitis and pneumonia.Symptoms of an RSV infection include coughing, sneezing, runny nose,fever, decrease in appetite, sore throat, headache and wheezing. RSV isthe most common cause of bronchiolitis and pneumonia in children underone year of age in the world, and can be the cause of tracheobronchitisin older children and adults. In the United States, between 75,000 and125,000 infants are hospitalized each year with RSV. Among adults olderthan 65 years of age, an estimated 14,000 deaths and 177,000hospitalizations have been attributed to RSV.

Treatment options for people infected with RSV are currently limited.Antibiotics, usually prescribed to treat bacterial infections, andover-the-counter medication are not effective in treating RSV and mayhelp only to relieve some of the symptoms. In severe cases, a nebulizedbronchodilator, such as albuterol, may be prescribed to relieve some ofthe symptoms, such as wheezing. RespiGam® (RSV-IGIV, Medlmmune, approvedfor high risk children younger than 24 months of age) and Synagis®(palivizumab, Medlmmune, approved for high risk children younger than 24months of age) have been approved for prophylactic use against RSV, andVirzole® (ribavirin by aerosol, ICN pharmaceuticals) have been approvedfor the treatment of RSV.

Parainfluenza viruses are typically negative-sense RNA viruses. Speciesof respirovirus include human parainfluenza viruses 1 and 3; and speciesof rubulavirus include human parainfluenza viruses 2 and 4. Humanparainfluenza virus includes four serotypes types (HPIV-1, HPIV-2,HPIV-3 and HPIV-4), and human parainfluenza virus 4 (HPIV-4) include twoantigenic subgroups, A and B. Human parainfluenza viruses can causeupper and lower respiratory tract infections. Human parainfluenza virus1 (HPIV-1) and human parainfluenza virus 2 (HPIV-2) can be associatedwith croup; human parainfluenza virus 3 (HPIV-3) can be associated withbronchiolitis and pneumonia. According to the Centers of Disease Controland Prevention (CDC), there are no vaccines against human parainfluenzaviruses.

A species of metapneumovirus is human metapneumovirus. Humanmetapneumovirus is a negative single-stranded RNA virus. Humanmetapneumovirus can cause respiratory tract infections, such as upperand lower respiratory tract infections in human, for example youngchildren.

Respiratory infections include colds, croup, pneumonia, bronchitis andbronchiolitis. Symptoms can include a cough, runny nose, nasalcongestion, sore throat, fever, difficulty breathing, abnormally rapidbreathing, wheezing vomiting, diarrhea and ear infections.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used herein, any “R” group(s) such as, without limitation, R^(1A),R^(2A), R^(3A), R^(4A), R^(5A), R^(6A), R^(7A), R^(8A), R^(9A), R^(10A),R^(11A), R^(12A), R^(13A), R^(14A), R^(15A), R^(16A), R^(17A), R^(18A),R^(19A), R^(20A), R^(21A), R^(22A), R^(23A), R^(24A), R^(25A), R^(26A),R^(27A), R^(28A), R^(29A), R^(30A), R^(31A), R^(32A), R^(33A), R^(34A),R^(35A), R^(36A), R^(37A) and R^(38A) represent substituents that can beattached to the indicated atom. An R group may be substituted orunsubstituted. If two “R” groups are described as being “taken together”the R groups and the atoms they are attached to can form a cycloalkyl,cycloalkenyl, aryl, heteroaryl or heterocycle. For example, withoutlimitation, if R^(a) and R^(b) of an NR^(a)R^(b) group are indicated tobe “taken together,” it means that they are covalently bonded to oneanother to form a ring:

In addition, if two “R” groups are described as being “taken together”with the atom(s) to which they are attached to form a ring as analternative, the R groups are not limited to the variables orsubstituents defined previously.

Whenever a group is described as being “optionally substituted” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“unsubstituted or substituted” if substituted, the substituent(s) may beselected from one or more of the indicated substituents. If nosubstituents are indicated, it is meant that the indicated “optionallysubstituted” or “substituted” group may be substituted with one or moregroup(s) individually and independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy,acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl,haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, an amino, a mono-substituted amino group anda di-substituted amino group.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl,alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s)of the aryl, ring(s) of the heteroaryl or ring(s) of the heterocyclylcan contain from “a” to “b”, inclusive, carbon atoms. Thus, for example,a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—,CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated withregard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl,heteroaryl or heterocyclyl group, the broadest range described in thesedefinitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl andhexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds.Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. Analkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds.Examples of alkynyls include ethynyl and propynyl. An alkynyl group maybe unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s)or 3 to 8 atoms in the ring(s). A cycloalkenyl group may beunsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group.Examples of aryl groups include, but are not limited to, benzene,naphthalene and azulene. An aryl group may be substituted orunsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1 to 5heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. Aheteroaryl group may be substituted or unsubstituted.

As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatom(s) is anelement other than carbon including, but not limited to, oxygen, sulfur,and nitrogen. A heterocycle may further contain one or more carbonyl orthiocarbonyl functionalities, so as to make the definition includeoxo-systems and thio-systems such as lactams, lactones, cyclic imides,cyclic thioimides and cyclic carbamates. When composed of two or morerings, the rings may be joined together in a fused fashion.Additionally, any nitrogens in a heterocyclyl or a heteroalicyclyl maybe quaternized. Heterocyclyl or heteroalicyclic groups may beunsubstituted or substituted. Examples of such “heterocyclyl” or“heteroalicyclyl” groups include but are not limited to, 1,3-dioxin,1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane,1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole,1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, trioxane,hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline,isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline,thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine,piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone,pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran,tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide,thiamorpholine sulfone and their benzo-fused analogs (e.g.,benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The loweralkylene and aryl group of an aralkyl may be substituted orunsubstituted. Examples include but are not limited to benzyl,2-phenyl(alkyl), 3-phenyl(alkyl) and naphthyl(alkyl).

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group connected, as a substituent, via a lower alkylenegroup. The lower alkylene and heteroaryl group of heteroaralkyl may besubstituted or unsubstituted. Examples include but are not limited to2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl),pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl)and their benzo-fused analogs.

A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to aheterocyclic or a heteroalicyclylic group connected, as a substituent,via a lower alkylene group. The lower alkylene and heterocyclyl of aheteroalicyclyl(alkyl) may be substituted or unsubstituted. Examplesinclude but are not limited tetrahydro-2H-pyran-4-yl(methyl),piperidin-4-yl(ethyl), piperidin-4-yl(propyl),tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Examples include but are not limited to methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and butylene(—CH₂CH₂CH₂CH₂—). A lower alkylene group can be substituted by replacingone or more hydrogen of the lower alkylene group with a substituent(s)listed under the definition of “substituted.”

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxysare methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy maybe substituted or unsubstituted.

As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, analkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, assubstituents, via a carbonyl group. Examples include formyl, acetyl,propanoyl, benzoyl and acryl. An acyl may be substituted orunsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). Asulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) orheterocyclyl(alkyl), as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group whereineach X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein each X is a halogen, and R_(A) hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may besubstituted or unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may besubstituted or unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl,aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamylmay be substituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substitutedor unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl),heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substitutedor unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “nucleoside” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a compound composed of anoptionally substituted pentose moiety or modified pentose moietyattached to a heterocyclic base or tautomer thereof via a N-glycosidicbond, such as attached via the 9-position of a purine-base or the1-position of a pyrimidine-base. Examples include, but are not limitedto, a ribonucleoside comprising a ribose moiety and adeoxyribonucleoside comprising a deoxyribose moiety. A modified pentosemoiety is a pentose moiety in which an oxygen atom has been replacedwith a carbon and/or a carbon has been replaced with a sulfur or anoxygen atom. A “nucleoside” is a monomer that can have a substitutedbase and/or sugar moiety. Additionally, a nucleoside can be incorporatedinto larger DNA and/or RNA polymers and oligomers. In some instances,the nucleoside can be a nucleoside analog drug.

The term “nucleotide” is used herein in its ordinary sense as understoodby those skilled in the art, and refers to a nucleoside having aphosphate ester bound to the pentose moiety, for example, at the5′-position.

As used herein, the term “heterocyclic base” refers to an optionallysubstituted nitrogen-containing heterocyclyl that can be attached to anoptionally substituted pentose moiety or modified pentose moiety. Insome embodiments, the heterocyclic base can be selected from anoptionally substituted purine-base, an optionally substitutedpyrimidine-base and an optionally substituted triazole-base (forexample, a 1,2,4-triazole). The term “purine-base” is used herein in itsordinary sense as understood by those skilled in the art, and includesits tautomers. Similarly, the term “pyrimidine-base” is used herein inits ordinary sense as understood by those skilled in the art, andincludes its tautomers. A non-limiting list of optionally substitutedpurine-bases includes purine, adenine, guanine, hypoxanthine, xanthine,alloxanthine, 7-alkylguanine (e.g. 7-methylguanine), theobromine,caffeine, uric acid and isoguanine. Examples of pyrimidine-basesinclude, but are not limited to, cytosine, thymine, uracil,5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). Anexample of an optionally substituted triazole-base is1,2,4-triazole-3-carboxamide. Other non-limiting examples ofheterocyclic bases include diaminopurine, 8-oxo-N⁶-alkyladenine (e.g.,8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine,7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine,5-halouracil (e.g., 5-fluorouracil and 5-bromouracil),pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic basesdescribed in U.S. Pat. Nos. 5,432,272 and 7,125,855, which areincorporated herein by reference for the limited purpose of disclosingadditional heterocyclic bases. In some embodiments, a heterocyclic basecan be optionally substituted with an amine or an enol protectinggroup(s).

The term “—N-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via a main-chain amino or mono-substituted aminogroup. When the amino acid is attached in an —N-linked amino acid, oneof the hydrogens that is part of the main-chain amino ormono-substituted amino group is not present and the amino acid isattached via the nitrogen. N-linked amino acids can be substituted orunsubstituted.

The term “—N-linked amino acid ester derivative” refers to an amino acidin which a main-chain carboxylic acid group has been converted to anester group. In some embodiments, the ester group has a formula selectedfrom alkyl-O—C(═O)—, cycloalkyl-O—C(═O)—, aryl-O—C(═O)— andaryl(alkyl)-O—C(═O)—. A non-limiting list of ester groups includesubstituted and unsubstituted versions of the following:methyl-O—C(═O)—, ethyl-O—C(═O)—, n-propyl-O—C(═O)—, isopropyl-O—C(═O)—,n-butyl-O—C(═O)—, isobutyl-O—C(═O)—, tert-butyl-O—C(═O)—,neopentyl-O—C(═O)—, cyclopropyl-O—C(═O)—, cyclobutyl-O—C(═O)—,cyclopentyl-O—C(═O)—, cyclohexyl-O—C(═O)—, phenyl-O—C(═O)—,benzyl-O—C(═O)—, and naphthyl-O—C(═O)—. N-linked amino acid esterderivatives can be substituted or unsubstituted.

The term “—O-linked amino acid” refers to an amino acid that is attachedto the indicated moiety via the hydroxy from its main-chain carboxylicacid group. When the amino acid is attached in an —O-linked amino acid,the hydrogen that is part of the hydroxy from its main-chain carboxylicacid group is not present and the amino acid is attached via the oxygen.O-linked amino acids can be substituted or unsubstituted.

As used herein, the term “amino acid” refers to any amino acid (bothstandard and non-standard amino acids), including, but not limited to,α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examplesof suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. Additionalexamples of suitable amino acids include, but are not limited to,ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine.

The terms “phosphorothioate” and “phosphothioate” refer to a compound ofthe general formula

its protonated forms (for example,

and its tautomers (such as

As used herein, the term “phosphate” is used in its ordinary sense asunderstood by those skilled in the art, and includes its protonatedforms (for example,

As used herein, the terms “monophosphate,” “diphosphate,” and“triphosphate” are used in their ordinary sense as understood by thoseskilled in the art, and include protonated forms.

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl,tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes, and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic, acetic, succinic, lactic, malic,tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic,p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a sodium ora potassium salt, an alkaline earth metal salt, such as a calcium or amagnesium salt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine,cyclohexylamine, triethanolamine, ethylenediamine, and salts with aminoacids such as arginine and lysine.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction, but instead as merely intended to highlight alternative oradditional features that may or may not be utilized in a particularembodiment. In addition, the term “comprising” is to be interpretedsynonymously with the phrases “having at least” or “including at least”.When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition ordevice, the term “comprising” means that the compound, composition ordevice includes at least the recited features or components, but mayalso include additional features or components. Likewise, a group ofitems linked with the conjunction ‘and’ should not be read as requiringthat each and every one of those items be present in the grouping, butrather should be read as ‘and/or’ unless expressly stated otherwise.Similarly, a group of items linked with the conjunction ‘or’ should notbe read as requiring mutual exclusivity among that group, but rathershould be read as ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article “a” or “an” does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included. For example alltautomers of a phosphate and a phosphorothioate groups are intended tobe included. Examples of tautomers of a phosphorothioate include thefollowing:

Furthermore, all tautomers of heterocyclic bases known in the art areintended to be included, including tautomers of natural and non-naturalpurine-bases and pyrimidine-bases.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I),or a pharmaceutically acceptable salt of the foregoing:

wherein: B^(1A) can be an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;R^(A) can be hydrogen or deuterium; R^(1A) can be selected fromhydrogen, an optionally substituted acyl, an optionally substitutedO-linked amino acid,

R^(a1) and R^(a2) can be independently hydrogen or deuterium; R^(2A) canbe a C₁₋₆ azidoalkyl or a C₁₋₆ aminoalkyl; R^(3A) can be selected fromOH, —OC(═O)R″^(A) and an optionally substituted O-linked amino acid;R^(4A) can be halogen; R^(5A) can be hydrogen or halogen; R^(6A), R^(7A)and R^(8A) can be independently selected from absent, hydrogen, anoptionally substituted C₁₋₂₄ alkyl, an optionally substituted C₃₋₂₄alkenyl, an optionally substituted C₃₋₂₄ alkynyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆cycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aryl(C₁₋₆ alkyl), an optionallysubstituted *—(CR^(15A)R^(16A))_(p)—O—C₁₋₂₄ alkyl, an optionallysubstituted *—(CR^(17A)R^(18A))_(q)—O—C₁₋₂₄ alkenyl,

or R^(6A) can be

and R^(7A) can be absent or hydrogen; or R^(6A) and R^(7A) can be takentogether to form a moiety selected from an optionally substituted

and an optionally substituted

wherein the oxygens connected to R^(6A) and R^(7A), the phosphorus andthe moiety form a six-membered to ten-membered ring system; R^(9A) canbe independently selected from an optionally substituted C₁₋₂₄ alkyl, anoptionally substituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₃₋₆ cycloalkenyl, NR an optionally substituted N-linkedamino acid and an optionally substituted N-linked amino acid esterderivative; R^(10A) and R^(11A) can be independently an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative; R^(12A), R^(13A) and R^(14A) can beindependently absent or hydrogen; each R^(15A), each R^(16A), eachR^(17A) and each R^(18A) can be independently hydrogen, an optionallysubstituted C₁₋₂₄ alkyl or alkoxy; R^(19A), R^(20A), R^(22A) and R^(23A)can be independently selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl and an optionally substituted aryl; R^(21A) and R^(24A) canbe independently selected from hydrogen, an optionally substituted C₁₋₂₄alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl, an optionally substituted —O-monocyclicheterocyclyl and

R^(25A) and R^(29A) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;R^(26A) and R^(27A) can be independently —C≡N or an optionallysubstituted substituent selected from C₂₋₈ organylcarbonyl, C₂₋₈alkoxycarbonyl and C₂₋₈ organylaminocarbonyl; R^(28A) can be selectedfrom hydrogen, an optionally substituted C₁₋₂₄-alkyl, an optionallysubstituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄ alkynyl, anoptionally substituted C₃₋₆ cycloalkyl and an optionally substitutedC₃₋₆ cycloalkenyl; R^(30A) and R^(31A) can be independently selectedfrom hydrogen, an optionally substituted C₁₋₂₄-alkyl, an optionallysubstituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄ alkynyl, anoptionally substituted C₃₋₆ cycloalkyl and an optionally substitutedC₃₋₆ cycloalkenyl; R″^(A) can be an optionally substituted C₁₋₂₄-alkyl;m and t can be independently 0 or 1; p and q can be independentlyselected from 1, 2 and 3; r can be 1 or 2; s can be 0, 1, 2 or 3; u canbe 1 or 2; and Z^(1A), Z^(2A), Z^(3A) and Z^(4A) can be independently Oor S.

In some embodiments, R^(1A) can be

In some embodiments, R^(6A) and R^(7A) can be both hydrogen. In otherembodiments, R^(6A) and R^(7A) can be both absent. In still otherembodiments, at least one R^(6A) and R^(7A) can be absent. In yet stillother embodiments, at least one R^(6A) and R^(7A) can be hydrogen. Thoseskilled in the art understand that when R^(6A) and/or R^(7A) are absent,the associated oxygen(s) will have a negative charge. For example, whenR^(6A) is absent, the oxygen associated with R^(6A) will have a negativecharge. In some embodiments, Z^(1A) can be O (oxygen). In otherembodiments, Z^(1A) can be S (sulfur). In some embodiments, R^(1A) canbe a monophosphate. In other embodiments, R^(1A) can be amonothiophosphate.

In some embodiments, when R^(1A) is

one of R^(6A) and R^(7A) can be hydrogen, and the other of R^(6A) andR^(7A) can be selected from an optionally substituted C₁₋₂₄ alkyl, anoptionally substituted C₃₋₂₄ alkenyl, an optionally substituted C₃₋₂₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₃₋₆ cycloalkenyl, an optionally substituted aryl, anoptionally substituted heteroaryl and an optionally substitutedaryl(C₁₋₆ alkyl). In some embodiments, one of R^(6A) and R^(7A) can behydrogen, and the other of R^(6A) and R^(7A) can be an optionallysubstituted C₁₋₂₄ alkyl. In other embodiments, both R^(6A) and R^(7A)can be independently selected from an optionally substituted C₁₋₂₄alkyl, an optionally substituted C₃₋₂₄ alkenyl, an optionallysubstituted C₃₋₂₄ alkynyl, an optionally substituted C₃₋₆ cycloalkyl, anoptionally substituted C₃₋₆ cycloalkenyl, an optionally substitutedaryl, an optionally substituted heteroaryl and an optionally substitutedaryl(C₁₋₆ alkyl). In some embodiments, both R^(6A) and R^(7A) can be anoptionally substituted C₁₋₂₄ alkyl. In other embodiments, both R^(6A)and R^(7A) can be an optionally substituted C₃₋₂₄ alkenyl. In someembodiments, R^(6A) and R^(7A) can be independently an optionallysubstituted version of the following: myristoleyl, myristyl,palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl,α-linolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl,caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl andcerotyl.

In some embodiments, at least one of R^(6A) and R^(7A) can be*—(CR^(15A)R^(16A))_(p)—O—C₁₋₂₄ alkyl. In other embodiments, R^(6A) andR^(7A) can be both *—(CR^(15A)R^(16A))_(p)—O—C₁₋₂₄ alkyl. In someembodiments, each R^(15A) and each R^(16A) can be hydrogen. In otherembodiments, at least one of R^(15A) and R^(16A) can be an optionallysubstituted C₁₋₂₄ alkyl. In other embodiments, at least one of R^(15A)and R^(16A) can be an alkoxy (for example, benzoxy). In someembodiments, p can be 1. In other embodiments, p can be 2. In stillother embodiments, p can be 3.

In some embodiments, at least one of R^(6A) and R^(7A) can be*—(CR^(17A)R^(18A))_(q)—O—C₂-24 alkenyl. In other embodiments, R^(6A)and R^(7A) can be both *—(CR^(17A)R^(18A))_(q)—O—C₂₋₂₄ alkenyl. In someembodiments, each R^(17A) and each R^(18A) can be hydrogen. In otherembodiments, at least one of R^(17A) and R^(18A) can be an optionallysubstituted C₁₋₂₄ alkyl. In some embodiments, q can be 1. In otherembodiments, q can be 2. In still other embodiments, q can be 3. When atleast one of R^(6A) and R^(7A) is *—(CR^(15A)R^(16A))_(p)—O—C₁₋₂₄ alkylor *—(CR^(17A)R^(18A))_(q)—O—C₂₋₂₄ alkenyl, the C₁₋₂₄ alkyl can beselected from caprylyl, capryl, lauryl, myristyl, palmityl, stearyl,arachidyl, behenyl, lignoceryl, and cerotyl, and the C₂₋₂₄ alkenyl canbe selected from myristoleyl, palmitoleyl, sapienyl, oleyl, elaidyl,vaccenyl, linoleyl, α-linolenyl, arachidonyl, eicosapentaenyl, erucyland docosahexaenyl.

In some embodiments, when R^(1A) is

at least one of R^(6A) and R^(7A) can be selected from

and the other of R^(6A) and R^(7A) can be selected from absent,hydrogen, an optionally substituted C₁₋₂₄ alkyl, an optionallysubstituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄ alkynyl, anoptionally substituted C₃₋₆ cycloalkyl, an optionally substituted C₃₋₆cycloalkenyl, an optionally substituted aryl, an optionally substitutedheteroaryl and an optionally substituted aryl(C₁₋₆ alkyl).

In some embodiments, at least one of R^(6A) and R^(7A) can be

In some embodiments, both R^(6A) and R^(7A) can be

When one or both of R^(6A) and R^(7A) are

R^(19A) and R^(20A) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;and R^(21A) can be selected from hydrogen, an optionally substitutedC₁₋₂₄ alkyl, an optionally substituted aryl, an optionally substituted—O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, an optionallysubstituted —O-heteroaryl, an optionally substituted —O-monocyclicheterocyclyl and

In some embodiments, R^(19A) and R^(20A) can be hydrogen. In otherembodiments, at least one of R^(19A) and R^(20A) can be an optionallysubstituted C₁₋₂₄ alkyl or an optionally substituted aryl. In someembodiments, R^(21A) can be an optionally substituted C₁₋₂₄ alkyl. Inother embodiments, R^(21A) can be an optionally substituted aryl. Instill other embodiments, R^(21A) can be an optionally substituted—O—C₁₋₂₄ alkyl or an optionally substituted —O-aryl. In someembodiments, R^(21A) can be an optionally substituted —O—C₁₋₂₄ alkyl, anoptionally substituted —O-aryl, an optionally substituted —O-heteroarylor an optionally substituted —O-monocyclic heterocyclyl.

In some embodiments, both R^(6A) and R^(7A) can be

When one or both of R^(6A) and R^(7A) are

R^(22A) and R^(23A) can be independently selected from hydrogen, anoptionally substituted C₁₋₂₄ alkyl and an optionally substituted aryl;R^(24A) can be independently selected from hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl, anoptionally substituted —O-heteroaryl, an optionally substituted—O-monocyclic heterocyclyl and

and Z^(4A) can be independently O (oxygen) or S (sulfur). In someembodiments, R^(22A) and R^(23A) can be hydrogen. In other embodiments,at least one of R^(22A) and R^(23A) can be an optionally substitutedC₁₋₂₄ alkyl or an optionally substituted aryl. In some embodiments,R^(24A) can be an optionally substituted C₁₋₂₄ alkyl. In otherembodiments, R^(24A) can be an optionally substituted aryl. In stillother embodiments, R^(24A) can be an optionally substituted —O—C₁₋₂₄alkyl or an optionally substituted —O-aryl. In some embodiments, Z^(4A)can be O (oxygen). In other embodiments, Z^(4A) can be or S (sulfur). Insome embodiments, s can be 0. In other embodiments, s can be 1. In stillother embodiments, s can be 2. In yet still embodiments, s can be 3. Insome embodiments, s can be 0, and R^(24A) can be

In some embodiments, u can be 1. In other embodiments, u can be 2. Insome embodiments, one or both of R^(6A) and R^(7A) can beisopropyloxycarbonyloxymethyl (POC). In some embodiments, one or both ofR^(6A) and R^(7A) can be pivaloyloxymethyl (POM). In some embodiments,R^(6A) and R^(7A) can be both a isopropyloxycarbonyloxymethyl group, andform a bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug. In someembodiments, R^(6A) and R^(7A) can be both a pivaloyloxymethyl group,and form a bis(pivaloyloxymethyl) (bis(POM)) prodrug.

In some embodiments, both R^(6A) and R^(7A) can be

wherein R^(26A) and R^(27A) can be independently —C≡N or an optionallysubstituted substituent selected from C₂₋₈ organylcarbonyl, C₂₋₈alkoxycarbonyl and C₂₋₈ organylaminocarbonyl; R^(28A) can be selectedfrom hydrogen, an optionally substituted C₁₋₂₄-alkyl, an optionallysubstituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄ alkynyl, anoptionally substituted C₃₋₆ cycloalkyl and an optionally substitutedC₃₋₆ cycloalkenyl; and r can be 1 or 2.

In some embodiments, R^(6A) and R^(7A) can be both an optionallysubstituted aryl. In some embodiments, at least one of R^(6A) and R^(7A)can be an optionally substituted aryl. For example, both R^(6A) andR^(7A) can be an optionally substituted phenyl or an optionallysubstituted naphthyl. When substituted, the substituted aryl can besubstituted with 1, 2, 3 or more than 3 substituents. When more the twosubstituents are present, the substituents can be the same or different.In some embodiments, when at least one of R^(6A) and R^(7A) is asubstituted phenyl, the substituted phenyl can be a para-, ortho- ormeta-substituted phenyl.

In some embodiments, R^(6A) and R^(7A) can be both an optionallysubstituted aryl(C₁₋₆ alkyl). In some embodiments, at least one ofR^(6A) and R^(7A) can be an optionally substituted aryl(C₁₋₆ alkyl). Forexample, both R^(6A) and R^(7A) can be an optionally substituted benzyl.When substituted, the substituted benzyl group can be substituted with1, 2, 3 or more than 3 substituents. When more the two substituents arepresent, the substituents can be the same or different. In someembodiments, the aryl group of the aryl(C₁₋₆ alkyl) can be a para-,ortho- or meta-substituted phenyl.

In some embodiments, R^(6A) and R^(7A) can be both

In some embodiments, at least one of R^(6A) and R^(7A) can be

In some embodiments, R^(25A) can be hydrogen. In other embodiments,R^(25A) can be an optionally substituted C₁₋₂₄ alkyl. In still otherembodiments, R^(25A) can be an optionally substituted aryl. In someembodiments, R^(25A) can be a C₁₋₆ alkyl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained) and hexyl (branched and straight-chained). In someembodiments, t can be 0. In other embodiments, t can be 1. In someembodiments, one or both of R^(6A) and R^(7A) can be a S-acylthioethyl(SATE).

In some embodiments, R^(6A) and R^(7A) can be both

In some embodiments, at least one of R^(6A) and R^(7A) can be

In some embodiments, R^(29A) can be hydrogen. In other embodiments,R^(29A) can be an optionally substituted C₁₋₂₄ alkyl. In someembodiments, R^(29A) can be a C₁₋₄ alkyl, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl and t-butyl. In still otherembodiments, R^(29A) can be an optionally substituted aryl, such as anoptionally substituted phenyl or an optionally substituted naphthyl. Insome embodiments, R^(6A) and R^(7A) can be both a dioxolenone group andform a dioxolenone prodrug.

In some embodiments, R^(1A) can be

R^(6A) can be

R^(7A) can be absent or hydrogen; R^(12A), R^(13A) and R^(14A) can beindependently absent or hydrogen; and m can be 0 or 1. In someembodiments, m can be 0, and R^(7A), R^(12A) and R^(13A) can beindependently absent or hydrogen. In other embodiments, m can be 1, andR^(7A), R^(12A), R^(13A) and R^(14A) can be independently absent orhydrogen. Those skilled in the art understand that when m is 0, R^(6A)can be diphosphate, when Z^(1A) is oxygen, or an alpha-thiodiphosphate,when Z^(1A) is sulfur. Likewise, those skilled in the art understandthat when m is 1, R^(6A) can be triphosphate, when Z^(1A) is oxygen, oran alpha-thiotriphosphate, when Z^(1A) is sulfur.

In some embodiments, R^(6A) and R^(7A) can be taken together to form anoptionally substituted

For example, R^(1A) can be an optionally substituted

When substituted, the ring can be substituted 1, 2, 3 or 3 or moretimes. When substituted with multiple substituents, the substituents canbe the same or different. In some embodiments, when R^(1A) is

the ring can be substituted with an optionally substituted aryl groupand/or an optionally substituted heteroaryl. An example of a suitableheteroaryl is pyridinyl. In some embodiments, R^(6A) and R^(7A) can betaken together to form an optionally substituted

such as

wherein R^(32A) can be an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted heterocyclyl. Insome embodiments, R^(6A) and R^(7A) can form a cyclic1-aryl-1,3-propanyl ester (HepDirect) prodrug moiety.

In some embodiments, R^(6A) and R^(7A) can be taken together to form anoptionally substituted

wherein the oxygens connected to R^(6A) and R^(7A), the phosphorus andthe moiety form a six-membered to ten-membered ring system. Example ofan optionally substituted

In some embodiments, R^(6A) and R^(7A) can form a cyclosaligenyl(cycloSal) prodrug.

In some embodiments, R^(6A) and R^(7A) can be the same. In someembodiments, R^(6A) and R^(7A) can be different.

In some embodiments, Z^(1A) can be oxygen. In other embodiments, Z^(1A)can be sulfur.

In some embodiments, R^(1A) can be

In some embodiments, R^(8A) can be selected from absent, hydrogen, anoptionally substituted C₁₋₂₄ alkyl, an optionally substituted C₂₋₂₄alkenyl, an optionally substituted C₂₋₂₄ alkynyl, an optionallysubstituted C₃₋₆ cycloalkyl and an optionally substituted C₃₋₆cycloalkenyl; and R^(9A) can be independently selected from anoptionally substituted C₁₋₂₄ alkyl, an optionally substituted C₂₋₂₄alkenyl, an optionally substituted C₂₋₂₄ alkynyl, an optionallysubstituted C₃₋₆ cycloalkyl and an optionally substituted C₃₋₆cycloalkenyl.

In some embodiments, R^(8A) can be hydrogen, and R^(9A) can be anoptionally substituted C₁₋₆ alkyl. Examples of suitable C₁₋₆ alkylsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl (branched and straight-chained) and hexyl (branchedand straight-chained). In other embodiments, R^(8A) can be hydrogen, andR^(9A) can be NR^(30A)R^(31A), wherein R³⁰ and R³¹ can be independentlyselected from hydrogen, an optionally substituted C₁₋₂₄ alkyl, anoptionally substituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl and an optionallysubstituted C₃₋₆ cycloalkenyl.

In some embodiments, R^(8A) can be absent or hydrogen; and R^(9A) can bean optionally substituted N-linked amino acid or an optionallysubstituted N-linked amino acid ester derivative. In other embodiments,R^(8A) can be an optionally substituted aryl; and R^(9A) can be anoptionally substituted N-linked amino acid or an optionally substitutedN-linked amino acid ester derivative. In still other embodiments, R^(8A)can be an optionally substituted heteroaryl; and R^(9A) can be anoptionally substituted N-linked amino acid or an optionally substitutedN-linked amino acid ester derivative. In some embodiments, R^(9A) can beselected from alanine, asparagine, aspartate, cysteine, glutamate,glutamine, glycine, proline, serine, tyrosine, arginine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, threonine,tryptophan, valine and ester derivatives thereof. Examples of anoptionally substituted N-linked amino acid ester derivatives includeoptionally substituted versions of the following: alanine isopropylester, alanine cyclohexyl ester, alanine neopentyl ester, valineisopropyl ester and leucine isopropyl ester. In some embodiments, R^(9A)can have the structure

wherein R^(33A) can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R^(34A) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted C₁₀ aryl and anoptionally substituted aryl(C₁₋₆ alkyl); and R^(35A) can be hydrogen oran optionally substituted C₁₋₄-alkyl; or R^(34A) and R^(35A) can betaken together to form an optionally substituted C₃₋₆ cycloalkyl.

When R^(34A) is substituted, R^(34A) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R^(34A) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(34A) can be hydrogen. In other embodiments, R^(34A) canbe methyl. In some embodiments, R^(33A) can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained) and hexyl (branched and straight-chained). In someembodiments, R^(33A) can be methyl or isopropyl. In some embodiments,R^(33A) can be ethyl or neopentyl. In other embodiments, R^(33A) can bean optionally substituted C₃₋₆ cycloalkyl. Examples of optionallysubstituted C₃₋₆ cycloalkyl include optionally substituted variants ofthe following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Inan embodiment, R^(33A) can be an optionally substituted cyclohexyl. Instill other embodiments, R^(33A) can be an optionally substituted aryl,such as phenyl and naphthyl. In yet still other embodiments, R^(33A) canbe an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments,R^(33A) can be an optionally substituted benzyl. In some embodiments,R^(33A) can be an optionally substituted C₁₋₆ haloalkyl, for example,CF₃. In some embodiments, R^(35A) can be hydrogen. In other embodiments,R^(35A) can be an optionally substituted C₁₋₄-alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In anembodiment, R^(35A) can be methyl. In some embodiments, R^(34A) andR^(35A) can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups thatare selected for R^(34A) and R^(35A), the carbon to which R^(34A) andR^(35A) are attached may be a chiral center. In some embodiment, thecarbon to which R^(34A) and R^(35A) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(34A) and R^(35A)are attached may be a (S)-chiral center.

In some embodiments, when R^(1A) is

Z^(2A) can be O (oxygen). In other embodiments, when R^(1A) is

Z^(2A) can be S (sulfur). In some embodiments, when R^(1A) is

a compound of Formula (I) can be a phosphoramidate prodrug, such as anaryl phosphoramidate prodrug.

In some embodiments, R^(1A) can be

In some embodiments, R^(10A) and R^(11A) can be both an optionallysubstituted N-linked amino acid or an optionally substituted N-linkedamino acid ester derivative. In some embodiments, R^(10A) and R^(11A)can be independently selected from alanine, asparagine, aspartate,cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine,arginine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, tryptophan, valine and ester derivativesthereof. In some embodiments, R^(10A) and R^(11A) can be an optionallysubstituted version of the following: alanine isopropyl ester, alaninecyclohexyl ester, alanine neopentyl ester, valine isopropyl ester andleucine isopropyl ester. In some embodiments, R^(10A) and R^(11A) canindependently have the structure

wherein R^(36A) can be selected from hydrogen, an optionally substitutedC₁₋₆-alkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted aryl, an optionally substituted aryl(C₁₋₆ alkyl) and anoptionally substituted haloalkyl; R^(37A) can be selected from hydrogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₁₋₆haloalkyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₆ aryl, an optionally substituted Cm aryl and an optionallysubstituted aryl(C₁₋₆ alkyl); and R^(38A) can be hydrogen or anoptionally substituted C₁₋₄-alkyl; or R^(37A) and R^(38A) can be takentogether to form an optionally substituted C₃₋₆ cycloalkyl.

When R^(37A) is substituted, R^(37A) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R^(37A) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(37A) can be hydrogen. In other embodiments, R^(37A) canbe methyl. In some embodiments, R^(36A) can be an optionally substitutedC₁₋₆ alkyl. Examples of optionally substituted C₁₋₆-alkyls includeoptionally substituted variants of the following: methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched andstraight-chained) and hexyl (branched and straight-chained). In someembodiments, R^(36A) can be methyl or isopropyl. In some embodiments,R^(36A) can be ethyl or neopentyl. In other embodiments, R^(36A) can bean optionally substituted C₃₋₆ cycloalkyl. Examples of optionallysubstituted C₃₋₆ cycloalkyl include optionally substituted variants ofthe following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Inan embodiment, R^(36A) can be an optionally substituted cyclohexyl. Instill other embodiments, R^(36A) can be an optionally substituted aryl,such as phenyl and naphthyl. In yet still other embodiments, R^(36A) canbe an optionally substituted aryl(C₁₋₆ alkyl). In some embodiments,R^(36A) can be an optionally substituted benzyl. In some embodiments,R^(36A) can be an optionally substituted C₁₋₆ haloalkyl, for example,CF₃. In some embodiments, R^(38A) can be hydrogen. In other embodiments,R^(38A) can be an optionally substituted C₁₋₄-alkyl, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In anembodiment, R^(38A) can be methyl. In some embodiments, R^(37A) andR^(38A) can be taken together to form an optionally substituted C₃₋₆cycloalkyl. Examples of optionally substituted C₃₋₆ cycloalkyl includeoptionally substituted variants of the following: cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups thatare selected for R^(37A) and R^(38A), the carbon to which R^(37A) andR^(38A) are attached may be a chiral center. In some embodiment, thecarbon to which R^(37A) and R^(38A) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(37A) and R^(38A)are attached may be a (S)-chiral center.

Examples of suitable

groups include the following:

In some embodiments, R^(10A) and R^(11A) can be the same. In someembodiments, R^(10A) and R^(11A) can be different.

In some embodiments, Z^(3A) can be O (oxygen). In other embodiments,Z^(3A) can be S (sulfur). In some embodiments, when R^(1A) is

a compound of Formula (I) can be a phosphonic diamide prodrug.

In some embodiments, R^(1A) can be hydrogen. In some embodiments, R^(1A)can be an optionally substituted acyl. In other embodiments, R^(1A) canbe —C(═O)R^(39A), wherein R^(39A) can be selected from an optionallysubstituted C₁₋₁₂ alkyl, an optionally substituted C₂₋₁₂ alkenyl, anoptionally substituted C₂₋₁₂ alkynyl, an optionally substituted C₃₋₈cycloalkyl, an optionally substituted C₅₋₈ cycloalkenyl, an optionallysubstituted C₆₋₁₀ aryl, an optionally substituted heteroaryl, anoptionally substituted heterocyclyl, an optionally substituted aryl(C₁₋₆alkyl), an optionally substituted heteroaryl(C₁₋₆ alkyl) and anoptionally substituted heterocyclyl(C₁₋₆ alkyl). In some embodiments,R^(39A) can be a substituted C₁₋₁₂ alkyl. In other embodiments, R^(39A)can be an unsubstituted C₁₋₁₂ alkyl.

In still other embodiments, R^(1A) can be an optionally substitutedO-linked amino acid. Examples of suitable O-linked amino acids includealanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine,proline, serine, tyrosine, arginine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, threonine, tryptophan and valine.Additional examples of suitable amino acids include, but are not limitedto, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine. In some embodiments, the O-linkedamino acid can have the structure

wherein R^(40A) can be selected from hydrogen, an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, anoptionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆alkyl); and R^(41A) can be hydrogen or an optionally substitutedC₁₋₄-alkyl; or R^(40A) and R^(41A) can be taken together to form anoptionally substituted C₃₋₆ cycloalkyl. Those skilled in the artunderstand that when R^(1A) is an optionally substituted O-linked aminoacid, the oxygen of R^(1A)O— of Formula (I) is part of the optionallysubstituted O-linked amino acid. For example, when R^(1A) is

the oxygen indicated with “*” is the oxygen of R^(1A)O— of Formula (I).

When R^(40A) is substituted, R^(40A) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R^(40A) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(40A) can be hydrogen. In other embodiments, R^(40A) canbe methyl. In some embodiments, R^(41A) can be hydrogen. In otherembodiments, R^(41A) can be an optionally substituted C₁₋₄-alkyl, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.In an embodiment, R^(41A) can be methyl. Depending on the groups thatare selected for R^(40A) and R^(41A), the carbon to which R^(40A) andR^(41A) are attached may be a chiral center. In some embodiment, thecarbon to which R^(40A) and R^(41A) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(40A) and R^(41A)are attached may be a (S)-chiral center.

Examples of suitable

include the following:

As described herein, in some embodiments, R^(2A) can be a C₁₋₆azidoalkyl. For example, R^(2A) can be an azidomethyl, azidoethyl,azidopropyl, azidobutyl, azidopentyl or azidohexyl. In otherembodiments, R^(2A) can be a C₁₋₆ aminoalkyl, such as aminomethyl,aminoethyl, aminopropyl, aminobutyl, aminopentyl or aminohexyl.

The groups attached to the 3′-position of the pentose ring can vary. Insome embodiments, R^(3A) can be OH. In other embodiments, R^(3A) can bean optionally substituted O-linked amino acid. Examples of suitableO-linked amino acids include alanine, asparagine, aspartate, cysteine,glutamate, glutamine, glycine, proline, serine, tyrosine, arginine,histidine, isoleucine, leucine, lysine, methionine, phenylalanine,threonine, tryptophan and valine. Additional examples of suitable aminoacids include, but are not limited to, ornithine, hypusine,2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid,citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine andnorleucine. In some embodiments, the O-linked amino acid can have thestructure

wherein R^(42A) can be selected from hydrogen, an optionally substitutedC₁₋₆ alkyl, an optionally substituted C₁₋₆ haloalkyl, an optionallysubstituted C₃₋₆ cycloalkyl, an optionally substituted C₆ aryl, anoptionally substituted C₁₀ aryl and an optionally substituted aryl(C₁₋₆alkyl); and R^(43A) can be hydrogen or an optionally substitutedC₁₋₄-alkyl; or R^(42A) and R^(43A) can be taken together to form anoptionally substituted C₃₋₆ cycloalkyl.

When R^(42A) is substituted, R^(42A) can be substituted with one or moresubstituents selected from N-amido, mercapto, alkylthio, an optionallysubstituted aryl, hydroxy, an optionally substituted heteroaryl,O-carboxy and amino. In some embodiments, R^(42A) can be anunsubstituted C₁₋₆-alkyl, such as those described herein. In someembodiments, R^(42A) can be hydrogen. In other embodiments, R^(42A) canbe methyl. In some embodiments, R^(43A) can be hydrogen. In otherembodiments, R^(43A) can be an optionally substituted C₁₋₄-alkyl, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.In an embodiment, R^(43A) can be methyl. Depending on the groups thatare selected for R^(42A) and R^(43A), the carbon to which R^(42A) andR^(43A) are attached may be a chiral center. In some embodiment, thecarbon to which R^(42A) and R^(43A) are attached may be a (R)-chiralcenter. In other embodiments, the carbon to which R^(42A) and R^(43A)are attached may be a (S)-chiral center.

Examples of suitable

include the following:

In still other embodiments, R^(3A) can be —OC(═O)R″^(A), wherein R″^(A)can be an optionally substituted C₁₋₂₄ alkyl. In some embodiments,R″^(A) can be a substituted C₁₋₈ alkyl. In other embodiments, R″^(A) canbe an unsubstituted C₁₋₈ alkyl. In still other embodiments, R^(3A) canbe an optionally substituted —O-acyl. In yet still other embodiments,R^(3A) can be —OC(═O)R^(44A), wherein R^(44A) can be selected from anoptionally substituted C₁₋₁₂ alkyl, an optionally substituted C₂₋₁₂alkenyl, an optionally substituted C₂₋₁₂ alkynyl, an optionallysubstituted C₃₋₈ cycloalkyl, an optionally substituted C₅₋₈cycloalkenyl, an optionally substituted C₆₋₁₀ aryl, an optionallysubstituted heteroaryl, an optionally substituted heterocyclyl, anoptionally substituted aryl(C₁₋₆ alkyl), an optionally substitutedheteroaryl(C₁₋₆ alkyl) and an optionally substituted heterocyclyl(C₁₋₆alkyl). In some embodiments, R^(44A) can be a substituted C₁₋₁₂ alkyl.In other embodiments, R^(44A) can be an unsubstituted C₁₋₁₂ alkyl.

Various substituents can be present at the 2′-position of the pentosering. In some embodiments, R^(5A) can be hydrogen. In other embodiments,R^(5A) can be halogen, for example, fluoro or chloro. In someembodiments, R^(4A) can be halogen, such as fluoro or chloro. In someembodiments, R^(5A) can be hydrogen and R^(4A) can be halogen. In someembodiments, R^(5A) can be hydrogen and R^(4A) can be fluoro. In otherembodiments, R^(5A) can be hydrogen and R^(4A) can be chloro. In otherembodiments, R^(4A) and R^(5A) can both be halogen.

A variety of substituents can also be present at the 5′-position of thepentose ring. In some embodiments, both R^(a1) and R^(a2) can behydrogen. In other embodiments, R^(a1) can be hydrogen and R^(a2) can bedeuterium. In still other embodiments, both R^(a1) and R^(a2) can bedeuterium. For the 1′-position, in some embodiments, R^(A) can behydrogen. In other embodiments, R^(A) can be deuterium.

In some embodiments, B^(1A) cannot be a substituted or unsubstitutedthymine. In other embodiments, B^(1A) cannot be an unsubstituted uracil.In still other embodiments, B^(1A) cannot be cytosine. In someembodiments R^(4A) cannot be H. In some embodiments R^(4A) cannot be Hwhen B^(1A) is an optionally substituted cytosine or an optionallysubstituted thymine. In some embodiments, Z^(1A) cannot be

In some embodiments, R^(1A) cannot be hydrogen when R^(2A) isazidomethyl, R^(3A) is hydroxy, R^(4A) is halogen (for example, fluoro),R^(5A) is hydrogen, R^(A) is hydrogen and B^(1A) is uracil. In someembodiments, R^(1A) cannot be hydrogen when R^(2A) is H₂N-methyl, R^(3A)is hydroxy, R^(4A) is halogen (for example, fluoro), R^(5A) is hydrogen,R^(A) is hydrogen and B^(1A) is uracil. In some embodiments, when R^(2A)is azidomethyl, R^(3A) is hydroxy, R^(4A) is halogen (for example,fluoro), R^(5A) is hydrogen and R^(A) is hydrogen. then B^(1A) cannot beuracil. In some embodiments, when R^(2A) is H₂N-methyl, R^(3A) ishydroxy, R^(4A) is halogen (for example, fluoro), R^(5A) is hydrogen andR^(A) is hydrogen, then B^(1A) cannot be uracil. In some embodiments, acompound of Formula (I), or a pharmaceutically acceptable salt, cannotbe

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt, cannot be

Various optionally substituted heterocyclic bases can be attached to thepentose ring. In some embodiments, one or more of the amine and/or aminogroups may be protected with a suitable protecting group. For example,an amino group may be protected by transforming the amine and/or aminogroup to an amide or a carbamate. In some embodiments, an optionallysubstituted heterocyclic base or an optionally substituted heterocyclicbase with one or more protected amino groups can have one of thefollowing structures:

wherein: R^(A2) can be selected from hydrogen, halogen and NHR^(J2),wherein R^(J2) can be selected from hydrogen, —C(═O)R^(K2) and—C(═O)OR^(L2); R^(B2) can be halogen or NHR^(W2), wherein R^(w2) can beselected from hydrogen, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₃₋₈cycloalkyl, —C(═O)R^(M2) and —C(═O)OR^(N2); R^(C2) can be hydrogen orNHR^(O2), wherein R^(O2) can be selected from hydrogen, —C(═O)R^(P2) and—C(═O)OR^(Q2); R^(D2) can be selected from hydrogen, deuterium, halogen,an optionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; R^(E2) can beselected from hydrogen, hydroxy, an optionally substituted C₁₋₆ alkyl,an optionally substituted C₃₋₈ cycloalkyl, —C(═O)R^(R2) and—C(═O)OR^(S2); R^(F2) can be selected from hydrogen, halogen, anoptionally substituted C₁₋₆ alkyl, an optionally substituted C₂₋₆alkenyl and an optionally substituted C₂₋₆ alkynyl; Y² and Y³ can beindependently N (nitrogen) or CR¹², wherein R¹² can be selected fromhydrogen, halogen, an optionally substituted C₁₋₆-alkyl, an optionallysubstituted C₂₋₆-alkenyl and an optionally substituted C₂₋₆-alkynyl;R^(G2) can be an optionally substituted C₁₋₆ alkyl; R^(H2) can behydrogen or NHR^(T2), wherein R^(T2) can be independently selected fromhydrogen, —C(═O)R^(U2) and —C(═O)OR^(V2); and R^(K2), R^(L2), R^(M2),R^(N2), R^(P2), R^(Q2), R^(R2), R^(S2), R^(U2) and R^(V2) can beindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, C₆₋₁₀ aryl, heteroaryl, heterocyclyl,aryl(C₁₋₆ alkyl), heteroaryl(C₁₋₆ alkyl) and heterocyclyl(C₁₋₆ alkyl).In some embodiments, the structures shown above can be modified byreplacing one or more hydrogens with substituents selected from the listof substituents provided for the definition of “substituted.”

In some embodiments, B^(1A) can be

In other embodiments, B^(1A) can be

In still other embodiments, B^(1A) can be

such as

In yet still other embodiments, B^(1A) can be

for example,

In some embodiments, R^(D2) can be hydrogen. In other embodiments,B^(1A) can be

In some embodiments, R^(B2) can be NH₂. In other embodiments, R^(B2) canbe NHR^(W2), wherein R^(W2) can be —C(═O)R^(M2) or —C(═O)OR^(N2). Instill other embodiments, B^(1A) can be

In some embodiments, B^(1A) can be

In some embodiments, a compound of Formula (I) can have the structure:

or a pharmaceutically acceptable salt of the foregoing. In otherembodiments, a compound of Formula (I) can have the structure:

or a pharmaceutically acceptable salt of the foregoing. In someembodiments of this paragraph, B^(1A) can be an optionally substitutedpurine base. In other embodiments of this paragraph, B^(1A) can be anoptionally substituted pyrimidine base. In some embodiments of thisparagraph, B^(1A) can be guanine. In other embodiments of thisparagraph, B^(1A) can be thymine. In still other embodiments of thisparagraph, B^(1A) can be cytosine. In yet still other embodiments ofthis paragraph, B^(1A) can be uracil. In some embodiments of thisparagraph, B^(1A) can be adenine. In some embodiments of this paragraph,R^(1A) can be hydrogen. In other embodiments of this paragraph, R^(1A)can be an optionally substituted acyl. In still other embodiments ofthis paragraph, R^(1A) can be mono-, di- or tri-phosphate. In yet otherembodiments of this paragraph, R^(1A) can be phosphoramidate prodrug,such as an aryl phosphoramidate prodrug. In some embodiments of thisparagraph, R^(1A) can be an acyloxyalkyl ester phosphate prodrug. Inother embodiments of this paragraph, R^(1A) can be a S-acylthioethyl(SATE) prodrug. In still other embodiments, R^(1A) can be a phosphonicdiamide prodrug. In yet still other embodiments, of this paragraph,R^(1A) can be a cyclic 1-aryl-1,3-propanyl ester (HepDirect) prodrugmoiety. In some embodiments of this paragraph, R^(1A) be acyclosaligenyl (cycloSal) prodrug.

Examples of suitable compounds of Formula (I) include, but are notlimited to the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of suitable compounds of Formula (I) include, but arenot limited to the following:

or a pharmaceutically acceptable salt of the foregoing.

Additional examples of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Examples of a compound of Formula (I) include the following:

or a pharmaceutically acceptable salt of the foregoing.

Further examples of a compound of Formula (I) include, but are notlimited to the following:

or a pharmaceutically acceptable salt of the foregoing.

Synthesis

Compounds of Formula (I) and those described herein may be prepared invarious ways. Some compounds of Formula (I) can be obtained commerciallyand/or prepared utilizing known synthetic procedures. General syntheticroutes to the compounds of Formula (I), and some examples of startingmaterials used to synthesize the compounds of Formula (I) are shown anddescribed herein. The routes shown and described herein are illustrativeonly and are not intended, nor are they to be construed, to limit thescope of the claims in any manner whatsoever. Those skilled in the artwill be able to recognize modifications of the disclosed syntheses andto devise alternate routes based on the disclosures herein; all suchmodifications and alternate routes are within the scope of the claims.

Compounds of Formula (I), where R^(2A) is a C₁₋₆ azidoalkyl can beprepared from a nucleoside, for example, a nucleoside of Formula (A). InScheme 1, R^(a), R^(3a), R^(4a), R^(5a) and B^(1a) can be the same asR^(A), R^(3A), R^(4A), R^(5A) and B^(1A) as described herein for Formula(I), PG¹ can be a suitable protecting group and LG¹ can be a suitableleaving group. The 5′-position of the nucleoside can be oxidized to analdehyde using methods known to those skilled in the art. Suitableoxidation conditions include, but are not limited to, Moffatt oxidation,Swern oxidation and Corey-Kim oxidation; and suitable oxidizing agentsinclude, but are not limited to, Dess-Martin periodinane, IBX(2-iodoxybenzoic acid), TPAP/NMO (tetrapropylammoniumperruthenate/N-methylmorpholine N-oxide), Swern oxidation reagent, PCC(pyridinium chlorochromate), PDC (pyridinium dichromate), sodiumperiodate, Collin's reagent, ceric ammonium nitrate CAN, Na₂Cr₂O₇ inwater, Ag₂CO₃ on celite, hot HNO₃ in aqueous glyme, O₂-pyridine CuCl,Pb(OAc)₄-pyridine and benzoyl peroxide-NiBr₂. A hydroxymethyl group canbe added to the 4′-position of the pentose ring along with the reductionof the aldehyde to an alcohol. The hydroxymethyl group can be added viaa condensation reaction using formaldehyde and a base, such as sodiumhydroxide. After addition of the hydroxymethyl group, reduction of theintermediate compound with a 4′-hydroxymethyl group can be conductedusing a reducing reagent. Examples of suitable reducing agents include,but are not limited to, NaBH₄ and LiAlH₄. A suitable leaving group, suchas a triflate, can be formed by replacing the hydrogen of thehydroxymethyl group attached to the 4′-position, and the oxygen attachedto the 5′-position can be protected with a suitable protecting group(for example, by cyclization with the base, B^(1a), or with a separateprotecting group). The leaving group can be replaced with an azido groupusing a metal azide reagent, for example, sodium azide.

Compounds of Formula (I) having a phosphorus containing group attachedto the 5′-position of the pentose ring can be prepared using variousmethods known to those skilled in the art. Examples of methods are shownin Schemes 2 and 3. In Schemes 2 and 3, R^(a), R^(2a), R^(3a), R^(4a),R^(5a), and B^(1a) can be the same as R^(A), R^(2A), R^(3A), R^(4A),R^(5A) and as described herein for Formula (I). A phosphorus containingprecursor can be coupled to the nucleoside, for example, a compound ofFormula (B). As shown in Scheme 2, following the coupling of thephosphorus containing precursor, any leaving groups can be cleaved undersuitable conditions, such as hydrolysis. Further phosphorus containinggroups can be added using methods known to those skilled in the art, forexample using a pyrophosphate.

In some embodiments, an alkoxide can be generated from a compound ofFormula (C) using an organometallic reagent, such as a Grignard reagent.The alkoxide can be coupled to the phosphorus containing precursor.Suitable Grignard reagents are known to those skilled in the art andinclude, but are not limited to, alkylmagnesium chlorides andalkylmagnesium bromides. In some embodiments, an appropriate base can beused. Examples of suitable bases include, but are not limited to, anamine base, such as an alkylamine (including mono-, di- andtri-alkylamines (e.g., triethylamine)), optionally substituted pyridines(e.g. collidine) and optionally substituted imidazoles (e.g.,N-methylimidazole)). Alternatively, a phosphorus containing precursorcan be added to the nucleoside and form a phosphite. The phosphite canbe oxidized to a phosphate using conditions known to those skilled inthe art. Suitable conditions include, but are not limited to,meta-chloroperoxybenzoic acid (MCPBA) and iodine as the oxidizing agentand water as the oxygen donor.

A C₁₋₆ azidoalkyl at the 4′-position can be reduced to a C₁₋₆aminoalkyl. Various reduction agents/conditions known to those skilledin the art can be utilized. For example, the azido group can be reducedto an amino group via hydrogenation (for example, H₂—Pd/C orHCO₂NH₄—Pd/C), Staudinger Reaction, NaBH₄/CoCl₂.6H₂O, Fe/NH₄Cl orZn/NH₄Cl.

When compounds of Formula (I) have Z^(1A), Z^(2A) or Z^(3A) beingsulfur, the sulfur can be added in various manners known to thoseskilled in the art. In some embodiments, the sulfur can be part of thephosphorus containing precursor, for example,

Alternatively, the sulfur can be added using a sulfurization reagent.Suitable sulfurization agents are known to those skilled in the art, andinclude, but are not limited to, elemental sulfur, Lawesson's reagent,cyclooctasulfur, 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage'sreagent),3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione(DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfide (TEST).

Suitable phosphorus containing precursors can be commercially obtainedor prepared by synthetic methods known to those skilled in the art.Examples of general structures of phosphorus containing precursors areshown in Schemes 2 and 3.

During the synthesis of any of the compounds described herein, ifdesired, any hydroxy groups attached to the pentose ring, and any —NHand/or NH₂ groups present on the B^(1a), can be protected with one ormore suitable protecting groups. Suitable protecting groups aredescribed herein. For example, when R^(3a) is a hydroxy group, R^(3a)can be protected with a triarylmethyl group or a silyl group. Likewise,any —NH and/or NH₂ groups present on the B^(1a) can be protected, suchas with a triarylmethyl and a silyl group(s). Examples of triarylmethylgroups include but are not limited to, trityl, monomethoxytrityl (MMTr),4,4′-dimethoxytrityl (DMTr), 4,4′,4″-trimethoxytrityl (TMTr),4,4′,4″-tris-(benzoyloxy) trityl (TBTr), 4,4′,4″-tris(4,5-dichlorophthalimido) trityl (CPTr), 4,4′,4″-tris (levulinyloxy)trityl (TLTr), p-anisyl-1-naphthylphenylmethyl,di-o-anisyl-1-naphthylmethyl, p-tolyldipheylmethyl,3-(imidazolylmethyl)-4,4′-dimethoxytrityl, 9-phenylxanthen-9-yl (Pixyl),9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl,4-hexadecyloxytrityl, 4,4′-dioctadecyltrityl, 9-(4-octadecyloxyphenyl)xanthen-9-yl, 1,1′-bis-(4-methoxyphenyl)-1′-pyrenylmethyl,4,4′,4″-tris-(tert-butylphenyl) methyl (TTTr) and 4,4′-di-3,5-hexadienoxytrityl. Examples of silyl groups include, but are notlimited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS),tri-iso-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. Thoseskilled in the art will appreciate that groups attached to the pentosering and any —NH and/or NH₂ groups present on the B^(1a) can beprotected with various protecting groups, and any protecting groupspresent can be exchanged for other protecting groups. The selection andexchange of the protecting groups is within the skill of those ofordinary skill in the art. Any protecting group(s) can be removed bymethods known in the art, for example, with an acid (e.g., a mineral oran organic acid), a base or a fluoride source.

Pharmaceutical Compositions

Some embodiments described herein relates to a pharmaceuticalcomposition, that can include an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof.

The term “pharmaceutical composition” refers to a mixture of one or morecompounds disclosed herein with other chemical components, such asdiluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Pharmaceuticalcompositions can also be obtained by reacting compounds with inorganicor organic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, and salicylic acid. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture and/or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Multiple techniques of administering a compound exist in the artincluding, but not limited to, oral, rectal, topical, aerosol, injectionand parenteral delivery, including intramuscular, subcutaneous,intravenous, intramedullary injections, intrathecal, directintraventricular, intraperitoneal, intranasal and intraocularinjections.

One may also administer the compound in a local rather than systemicmanner, for example, via injection of the compound directly into theinfected area, often in a depot or sustained release formulation.Furthermore, one may administer the compound in a targeted drug deliverysystem, for example, in a liposome coated with a tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe organ.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compounddescribed herein formulated in a compatible pharmaceutical carrier mayalso be prepared, placed in an appropriate container, and labeled fortreatment of an indicated condition.

Methods of Use:

Some embodiments described herein relate to a method of ameliorating,treating and/or preventing a paramyxovirus viral infection, which caninclude administering to a subject an effective amount of one or morecompounds described herein, or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof). In someembodiments, the subject is identified as suffering from a paramyxovirusviral infection.

Other embodiments described herein relate to a method of inhibitingviral replication of a paramyxovirus, which can include contacting acell infected with the virus with an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof). For example, a compound of Formula (I), or apharmaceutically acceptable salt, can act as a chain-terminator andinhibit replication of the virus.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate aparamyxovirus infection. In some embodiments, an effective amount of oneor more compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to prevent aparamyxovirus infection. In some embodiments, an effective amount of oneor more compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit thereplication of a paramyxovirus. In some embodiments, an effective amountof one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto inhibit the polymerase complex of a paramyxovirus.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate an upperrespiratory viral infection caused by a paramyxovirus infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate a lowerrespiratory viral infection caused by a paramyxovirus infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate one or moresymptoms of an infection caused by a paramyxovirus infection (such asthose described herein).

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or amelioratebronchiolitis and/or tracheobronchitis due to a paramyxovirus infection.In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate pneumoniadue to a paramyxovirus infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedtreat and/or ameliorate croup due to a paramyxovirus infection.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate arespiratory syncytial viral (RSV) infection. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to prevent a respiratory syncytial viral infection.In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication of arespiratory syncytial virus. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit the RSVpolymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate an upperrespiratory viral infection caused by RSV infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate a lowerrespiratory viral infection caused by RSV infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate one or moresymptoms of an infection caused by RSV infection (such as thosedescribed herein).

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or amelioratebronchiolitis and/or tracheobronchitis due to a RSV infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate pneumoniadue to a RSV infection. In some embodiments, an effective amount of oneor more compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used treat and/orameliorate croup due to a RSV infection.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a HPIV-1infection and/or HPIV-3 infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto prevent a HPIV-1 infection and/or HPIV-3 infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used to inhibit the replication of HPIV-1 and/or HPIV-3.In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the HPIV-1 polymerasecomplex and/or HPIV-3 polymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate a HPIV-2infection and/or HPIV-4 infection. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto prevent a HPIV-2 infection and/or HPIV-4 infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to inhibit the replication ofHPIV-2 and/or HPIV-4. In some embodiments, an effective amount of one ormore compounds of Formula (I), or a pharmaceutically acceptable saltthereof, and/or a pharmaceutical composition that includes one or morecompounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit theHPIV-2 polymerase complex and/or HPIV-4 polymerase complex.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used to treat and/or ameliorate ametapneumoviral infection. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to prevent ametapneumoviral infection. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used to inhibit thereplication of a metapneumovirus. In some embodiments, an effectiveamount of one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, and/or a pharmaceutical composition thatincludes one or more compounds described herein (e.g., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof) can be usedto inhibit the metapneumovirus polymerase complex. In some embodiments,including those of this paragraph, the metapneumovirus can be a humanmetapneumovirus.

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate an upperrespiratory viral infection caused by a virus selected from a RSV virus,a parainfluenza virus and a metapneumovirus. In some embodiments, aneffective amount of one or more compounds of Formula (I), or apharmaceutically acceptable salt thereof, and/or a pharmaceuticalcomposition that includes one or more compounds described herein (e.g.,a compound of Formula (I), or a pharmaceutically acceptable saltthereof) can be used treat and/or ameliorate a lower respiratory viralinfection caused by a virus selected from a RSV virus, a parainfluenzavirus and a metapneumovirus. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used treat and/orameliorate one or more symptoms of an infection caused by a virusselected from a RSV virus, a parainfluenza virus and a metapneumovirus(such as those described herein).

In some embodiments, an effective amount of one or more compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or amelioratebronchiolitis and/or tracheobronchitis due to a RSV virus infection, aparainfluenza virus infection and a metapneumovirus infection. In someembodiments, an effective amount of one or more compounds of Formula(I), or a pharmaceutically acceptable salt thereof, and/or apharmaceutical composition that includes one or more compounds describedherein (e.g., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof) can be used treat and/or ameliorate pneumoniadue to a RSV virus infection, a parainfluenza virus infection and ametapneumovirus infection. In some embodiments, an effective amount ofone or more compounds of Formula (I), or a pharmaceutically acceptablesalt thereof, and/or a pharmaceutical composition that includes one ormore compounds described herein (e.g., a compound of Formula (I), or apharmaceutically acceptable salt thereof) can be used treat and/orameliorate croup due to a RSV virus infection, a parainfluenza virusinfection and a metapneumovirus infection.

The one or more compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, that can be used to treat, ameliorate and/orprevent a paramyxovirus viral infection can be a compound of Formula(I), or pharmaceutically acceptable salt thereof, provided in any of theembodiments described in paragraphs [0083]-[0130].

As used herein, the terms “prevent” and “preventing,” mean lowering theefficiency of viral replication and/or inhibiting viral replication to agreater degree in a subject who receives the compound compared to asubject who does not receive the compound. Examples of forms ofprevention include prophylactic administration to a subject who has beenor may be exposed to an infectious agent, such as a paramyxovirus (e.g.,RSV).

As used herein, the terms “treat,” “treating,” “treatment,”“therapeutic,” and “therapy” do not necessarily mean total cure orabolition of the disease or condition. Any alleviation of any undesiredsigns or symptoms of a disease or condition, to any extent can beconsidered treatment and/or therapy. Furthermore, treatment may includeacts that may worsen the subject's overall feeling of well-being orappearance.

The terms “therapeutically effective amount” and “effective amount” areused to indicate an amount of an active compound, or pharmaceuticalagent, that elicits the biological or medicinal response indicated. Forexample, an effective amount of compound can be the amount needed toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the signs orsymptoms of the disease being treated. Determination of an effectiveamount is well within the capability of those skilled in the art, inview of the disclosure provided herein. The therapeutically effectiveamount of the compounds disclosed herein required as a dose will dependon the route of administration, the type of animal, including human,being treated, and the physical characteristics of the specific animalunder consideration. The dose can be tailored to achieve a desiredeffect, but will depend on such factors as weight, diet, concurrentmedication and other factors which those skilled in the medical artswill recognize.

Various indicators for determining the effectiveness of a method fortreating a paramyxovirus viral infection are known to those skilled inthe art. Example of suitable indicators include, but are not limited to,a reduction in viral load, a reduction in viral replication, a reductionin time to seroconversion (virus undetectable in patient serum), areduction of morbidity or mortality in clinical outcomes, and/or otherindicator of disease response.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to reduce viral titers to undetectable levels, for example, toabout 1000 to about 5000, to about 500 to about 1000, or to about 100 toabout 500 genome copies/mL serum. In some embodiments, an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is an amount that is effective to reduce viral loadcompared to the viral load before administration of the compound ofFormula (I), or a pharmaceutically acceptable salt thereof. For example,wherein the viral load is measure before administration of the compoundof Formula (I), or a pharmaceutically acceptable salt thereof, and againafter completion of the treatment regime with the compound of Formula(I), or a pharmaceutically acceptable salt thereof (for example, 1 weekafter completion). In some embodiments, an effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be an amount that is effective to reduce viral load to lower thanabout 100 genome copies/mL serum. In some embodiments, an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is an amount that is effective to achieve a reduction inviral titer in the serum of the subject in the range of about 1.5-log toabout a 2.5-log reduction, about a 3-log to about a 4-log reduction, ora greater than about 5-log reduction compared to the viral load beforeadministration of the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. For example, wherein the viral load is measurebefore administration of the compound of Formula (I), or apharmaceutically acceptable salt thereof, and again after completion ofthe treatment regime with the compound of Formula (I), or apharmaceutically acceptable salt thereof (for example, 1 week aftercompletion).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can result in at least a 1, 2, 3, 4, 5, 10, 15,20, 25, 50, 75, 100-fold or more reduction in the replication of aparamyxovirus relative to pre-treatment levels in a subject, asdetermined after completion of the treatment regime (for example, 1 weekafter completion). In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can result in a reduction ofthe replication of a paramyxovirus relative to pre-treatment levels inthe range of about 2 to about 5 fold, about 10 to about 20 fold, about15 to about 40 fold, or about 50 to about 100 fold. In some embodiments,a compound of Formula (I), or a pharmaceutically acceptable saltthereof, can result in a reduction of paramyxovirus replication in therange of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log,3 log to 3.5 log or 3.5 to 4 log more reduction of paramyxovirusreplication compared to the reduction of paramyxovirus reductionachieved by ribavirin (Virazole®), or may achieve the same reduction asthat of ribavirin (Virazole®) therapy in a shorter period of time, forexample, in one week, two weeks, one month, two months, or three months,as compared to the reduction achieved after six months of ribavirin(Virazole®) therapy.

In some embodiments, an effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, is an amount that iseffective to achieve a sustained viral response, for example,non-detectable or substantially non-detectable paramyxovirus RNA (e.g.,less than about 500, less than about 400, less than about 200, or lessthan about 100 genome copies per milliliter serum) is found in thesubject's serum for a period of at least about one week, two weeks, onemonth, at least about two months, at least about three months, at leastabout four months, at least about five months, or at least about sixmonths following cessation of therapy.

After a period of time, infectious agents can develop resistance to oneor more therapeutic agents. The term “resistance” as used herein refersto a viral strain displaying a delayed, lessened and/or null response toa therapeutic agent(s). For example, after treatment with an antiviralagent, the viral load of a subject infected with a resistant virus maybe reduced to a lesser degree compared to the amount in viral loadreduction exhibited by a subject infected with a non-resistant strain.In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered to a subject infected withRSV that is resistant to one or more different anti-RSV agents (forexample, ribavirin) to ameliorate and/or treat a RSV infection. In someembodiments, development of one or more resistant RSV strains can bedelayed when subjects are treated with a compound of Formula (I), or apharmaceutically acceptable salt thereof, compared to the development ofone or more RSV strains resistant to other anti-RSV agents.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can decrease the percentage of subjects thatexperience complications from a RSV viral infection compared to thepercentage of subjects that experience complication being treated withribavirin. For example, the percentage of subjects being treated with acompound of Formula (I), or a pharmaceutically acceptable salt thereof,that experience complications can be 10%, 25%, 40%, 50%, 60%, 70%, 80%and 90% less compared to subjects being treated with ribavirin.

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition that includes acompound described herein, can be used in combination with one or moreadditional agent(s). In some embodiments, a compound of Formula (I), ora pharmaceutically acceptable salt thereof, can be used in combinationwith one or more agents currently used for treating RSV. For example,the additional agent can be ribavirin, palivizumab and RSV-IGIV. For thetreatment of RSV, additional agents include but are not limited toALN-RSV01 (an siRNA agent with the sense strand sequence (5′ to 3′)GGCUCUUAGCAAAGUCAAGdTdT (SEQ ID NO. 1) and the antisense strand sequence(5′ to 3′) CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 2), AlnylamPharmaceuticals, U.S. Publication No. 2009/0238772, filed Dec. 15,2008), BMS-433771(1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one),RFI-6414,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic-acid),RSV604((S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea),MDT-6375,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol),BTA9881((R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[1′,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one),TMC-353121(2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol)(Tibotec), MBX-300([2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate),YM-53403 (6-{4-[(biphenyl-2-ylcarbonyl)amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide),motavizumab (Medi-524, Medlmmune), Medi-559 (Recombinant RSV A2cp248/404/1030/ΔSH), Medi-534 (vector vaccine candidate recombinantbovine/human parainfluenza virus type 3 (PIV3)/RSV F2), Medi-557, RV568and a RSV-F Particle Vaccine (Novavax).

In some embodiments, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, can be administered with one or more additionalagent(s) together in a single pharmaceutical composition. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered with one or more additional agent(s)as two or more separate pharmaceutical compositions. For example, acompound of Formula (I), or a pharmaceutically acceptable salt thereof,can be administered in one pharmaceutical composition, and at least oneof the additional agents can be administered in a second pharmaceuticalcomposition. If there are at least two additional agents, one or more ofthe additional agents can be in a first pharmaceutical composition thatincludes a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one of the other additional agent(s) can bein a second pharmaceutical composition.

The order of administration of a compound of Formula (I), or apharmaceutically acceptable salt thereof, with one or more additionalagent(s) can vary. In some embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered prior toall additional agents. In other embodiments, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, can be administered priorto at least one additional agent. In still other embodiments, a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, can beadministered concomitantly with one or more additional agent(s). In yetstill other embodiments, a compound of Formula (I), or apharmaceutically acceptable salt thereof, can be administered subsequentto the administration of at least one additional agent. In someembodiments, a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, can be administered subsequent to the administration ofall additional agents.

A potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described in paragraph [0173], includingpharmaceutically acceptable salts and prodrugs thereof, may be areduction in the required amount(s) of one or more compounds ofparagraph [0173] (including pharmaceutically acceptable salts andprodrugs thereof) that is effective in treating a disease conditiondisclosed herein (for example, RSV), as compared to the amount requiredto achieve same therapeutic result when one or more compounds describedin paragraph [0173], including pharmaceutically acceptable salts andprodrugs thereof, are administered without a compound of Formula (I), ora pharmaceutically acceptable salt thereof. For example, the amount of acompound described in paragraph [0173], including a pharmaceuticallyacceptable salt and prodrug thereof, can be less compared to the amountof the compound described in paragraph [0173], including apharmaceutically acceptable salt and prodrug thereof, needed to achievethe same viral load reduction when administered as a monotherapy.Another potential advantage of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described in paragraph [0173], includingpharmaceutically acceptable salts and prodrugs thereof, is that the useof two or more compounds having different mechanism of actions cancreate a higher barrier to the development of resistant viral strainscompared to the barrier when a compound is administered as monotherapy.

Additional advantages of utilizing a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with one ormore additional agent(s) described in paragraph [0173], includingpharmaceutically acceptable salts and prodrugs thereof, may includelittle to no cross resistance between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described in paragraph [0173] (including pharmaceuticallyacceptable salts and prodrugs thereof); different routes for eliminationof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, and one or more additional agent(s) described in paragraph[0173] (including pharmaceutically acceptable salts and prodrugsthereof); little to no overlapping toxicities between a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and one ormore additional agent(s) described in paragraph [0173] (includingpharmaceutically acceptable salts and prodrugs thereof); little to nosignificant effects on cytochrome P450; and/or little to nopharmacokinetic interactions between a compound of Formula (I), or apharmaceutically acceptable salt thereof, and one or more additionalagent(s) described in paragraph [0173] (including pharmaceuticallyacceptable salts and prodrugs thereof).

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.The determination of effective dosage levels, that is the dosage levelsnecessary to achieve the desired result, can be accomplished by oneskilled in the art using routine methods, for example, human clinicaltrials and in vitro studies.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The daily dosage regimen for an adult human patientmay be, for example, an oral dose of between 0.01 mg and 3000 mg of eachactive ingredient, preferably between 1 mg and 700 mg, e.g. 5 to 200 mg.The dosage may be a single one or a series of two or more given in thecourse of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations. Dosageintervals can also be determined using MEC value. Compositions should beadministered using a regimen which maintains plasma levels above the MECfor 10-90% of the time, preferably between 30-90% and most preferablybetween 50-90%. In cases of local administration or selective uptake,the effective local concentration of the drug may not be related toplasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Example 1 Preparation of Compound 1A

Preparation of (1-2):

To a solution of 1-1 (50 g, 203 mmol) in anhydrous pyridine (200 mL) wasadded TBDPS-Cl (83.7 g, 304 mmol). The reaction was allowed to proceedovernight at R.T. The solution was concentrated under low pressure togive a residue, which was partitioned between ethyl acetate and water.The organic layer was separated, washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure to give 5′-OTBDPS etheras a white foam (94 g).

To a solution of the 5′-OTBDPS ether (94.0 g, 194.2 mmol) in anhydrousDCM (300 mL) were added silver nitrate (66.03 g, 388.4 mmol) andcollidine (235 mL, 1.94 mol). The mixture was stirred at R.T. After 15mins, the mixture was cooled to 0° C., and monomethoxytrityl chloride(239.3 g, 776.8 mmol) was added as a single portion. After being stirredovernight at R.T., the mixture was filtered through Celite and thefiltrate was diluted with TBME. The solution was washed successivelywith 1M citric acid, diluted brine and 5% sodium bicarbonate. Theorganic solution was dried over sodium sulfate and concentrated undervacuum to give the fully protected intermediate as a yellow foam.

This fully protected intermediate was dissolved in toluene (100 mL) andthe solution was concentrated under reduced pressure. The residue wasdissolved in anhydrous THF (250 mL) and treated with TBAF (60 g, 233mmol). The mixture was stirred for 2 h at R.T., and the solvent wasremoved under reduced pressure. The residue was taken into ethyl acetateand the solution was washed first with saturated sodium bicarbonate andthen with brine. After being dried over magnesium sulfate, the solventwas removed in vacuum and the residue was purified by columnchromatography (50% EA in PE) to give 1-2 (91 g, 86.4%) as a white foam.

Preparation of (1-3):

To a solution of 1-2 (13.5 g, 26 mmol) in DCM (100 mL) was addedpyridine (6.17 mL, 78 mmol). The solution was cooled to 0° C., andDess-Martin periodinane (33.8 g, 78 mmol) was added as a single portion.The reaction mixture was stirred for 4 h at R.T., and quenched by theaddition of Na₂S₂O₃ solution (4%) and sodium bicarbonate aqueoussolution (4%) (the solution was adjusted to pH 6, ˜150 mL). The mixturewas stirred for 15 mins. The organic layer was separated, washed withdiluted brine and concentrated under reduced pressure. The residue wasdissolved in dioxane (100 mL) and the solution was treated with 37%aqueous formaldehyde (21.2 g, 10 eq.) and 2N aqueous sodium hydroxide(10 eq.). The reaction mixture was stirred at R.T., overnight. Afterstirring for 0.5 h at R.T., the excess of aqueous sodium hydroxide wasremoved with saturated NH₄Cl (˜150 mL). The mixture was concentratedunder reduced pressure, and the residue was partitioned between ethylacetate and 5% sodium bicarbonate. The organic phase was separated,washed with brine, dried over magnesium sulfate and concentrated. Theresidue was purified by column chromatography (2% MeOH in DCM) to givethe diol 1-3 (9.2 g, 83.6%) as a white foam.

Preparation of (1-4):

Compound 1-3 (23 g, 42.0 mmol) was co-evaporated with toluene twice. Theresidue was dissolved in anhydrous DCM (250 mL) and pyridine (20 mL).The solution was cooled to 0° C., and triflic anhydride (24.9 g, 88.1mmol) was added dropwise over 10 mins. At this temperature, the reactionwas stirred for 40 mins. The reaction was monitored by TLC (PE:EA=2:1and DCM: MeOH, 15:1). After completion, the reaction mixture wasquenched with water (50 mL) at 0° C. The mixture was stirred for 30mins, and extracted with EA. The organic phase was dried over Na₂SO₄ andfiltered through a silica gel pad. The filtrate was concentrated underreduced pressure, and the residue was purified by column chromatography(50% EA in PE) to give 1-4 (30.0 g, 88.3%) as a brown foam.

Preparation of (1-5):

To a stirred solution of 1-4 (4.4 g, 5.42 mmol) in anhydrous DMF (50 mL)was added NaH (260 mg, 6.5 mmol) at 0° C. under nitrogen atmosphere. Thesolution was stirred at R.T., for 1.5 h. The solution was used for thenext step without any further workup.

Preparation of (1-6):

To the stirred solution was added NaN₃ (1.5 g, 21.68 mmol) at 0° C.under nitrogen atmosphere, and the resulting solution was stirred atR.T. for 1.5 h. The reaction was quenched with water, extracted with EA,washed with brine, and dried over MgSO₄. The concentrated organic phasewas used for the next step without further purification.

Preparation of (1-7):

To a solution of 1-6 (3.0 g, 5.4 mmol) in anhydrous 1,4-dioxane (18 mL)was added NaOH (5.4 mL, 2M in water) at R.T. The reaction mixture wasstirred at R.T. for 3 h. The reaction was diluted with EA, washed withbrine, and dried over MgSO₄. The concentrated organic phase was purifiedon a silica gel column (30% EA in PE) to give 1-7 (2.9 g, 93%) as awhite foam.

Preparation of (1A):

Compound 1-7 (520 mg, 0.90 mmol) was dissolved in 80% of HCOOH (20 mL)at R.T. The mixture was stirred for 3 h, and monitored by TLC. Thesolvent was removed and the residue was treated with MeOH and toluenefor 3 times. NH₃/MeOH was added, and the reaction mixture was stirred atR.T., for 5 mins. The solvent was concentrated to dryness and theresidue was purified by column chromatography to give 1A (120 mg, 44.4%)as a white solid. ESI-LCMS: m/z 302.0 [M+H]⁺, 324.0 [M+Na]⁺.

Example 2 Preparation of Compound 2A

Preparation of (2-1):

To a stirred solution of 1-7 (1.1 g, 2.88 mmol) in anhydrous DCM (10 mL)was added MMTrCl (1.77 g, 5.76 mmol), AgNO₃ (1.47 g, 8.64 mmol) andcollidine (1.05 g, 8.64 mmol) at 25° C. under a N₂ atmosphere. Thereaction was refluxed for 12 h. MeOH (20 mL) was added and the solventwas removed to dryness. The residue was purified on a silica gel column(20% EA in PE) to give 2-1 (1.6 g, 85.1%) as a white foam.

Preparation of (2-2):

To a stirred solution of 2-1 (800 mg, 0.947 mmol) in anhydrous MeCN (10mL) were added TPSCl (570 mg, 1.89 mmol), DMAP (230 mg, 1.89 mmol) andTEA (190 mg, 1.89 mmol) at R.T. The mixture was stirred for 12 h. NH₄OH(25 mL) was added and the mixture was stirred for 2 h. The solvent wasremoved, and the residue was purified on a silica gel column as a yellowfoam. Further purification by prep-TLC gave 2-2 (700 mg, 87.1%) as awhite solid.

Preparation of (2A):

Compound 2-2 (300 mg, 0.355 mmol) was dissolved in 80% of HCOOH (5 mL)at R.T. The mixture was stirred for 3 h, and monitored by TLC. Thesolvent was then removed and the residue was treated with MeOH andtoluene (3 times). NH₃/MeOH was added and the mixture was stirred atR.T., for 5 mins. The solvent was removed and the residue was purifiedby column chromatography to give 2A (124 mg, 82.6%) as a white solid.ESI-LCMS: m/z 301.0 [M+H]⁺, 601.0 [2M+H]⁺.

Example 3 Preparation of Compound 14A

Preparation of (AA-2):

AA-1 (2.20 g, 3.84 mmol) was dissolved in 80% HCOOH (40 mL) at R.T. (18°C.). The mixture was stirred at R.T. for 12 h. The solvent was removedat low pressure. The residue was purified by column chromatography using50% EA in Hexane to give AA-2 (1.05 g, 91.3%) as a white solid.

Preparation of (AA-3):

To a stirred solution of AA-2 (1 g, 3.32 mmol) in anhydrous pyridine (20mL) was added TBSCl (747 mg, 4.98 mmol) and imidazole (451 mg, 6.64mmol) at R.T. (16° C.) under N₂ atmosphere. The mixture was stirred atR.T. for 4 h. The resulting solution was concentrated to dryness underreduced pressure, and the residue was dissolved in EA (100 mL). Thesolution was washed with sat. NaHCO₃ solution and brine, and dried overanhydrous MgSO₄. The solution was concentrated to dryness, and theresidue was purified on a silica gel column using 20% EA in Hexane togive AA-3 (1.4 g, 79.5%) as a white solid.

Preparation of (AA-4):

To a stirred solution of AA-3 (1.50 g, 2.83 mmol, 1.00 eq.) in anhydrousCH₃CN (28 mL) was added TPSCl (1.71 g, 5.80 mmol, 2.05 eq.), DMAP(691.70 mg, 5.66 mmol, 2.00 eq.) and TEA (573.00 mg, 5.66 mmol, 2.00eq.) at R.T. (15° C.). The mixture was stirred for 2 h. NH₃.H₂O (20 mL)was added, and the mixture was stirred for 3 h. The mixture wasextracted with EA (3×60 mL). The organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated at low pressure. Theresidue was purified on a silica gel column (30% EA in PE) to give AA-4(2.3 g, crude) as a yellow foam.

Preparation of (AA-5):

To a stirred solution of AA-4 (1.90 g, 2.34 mmol) in anhydrous DCM (20mL) was added DMTrCl (1.82 g, 3.49 mmol) and 2,4,6-trimethylpyridine(1.00 g, 8.25 mmol) at R.T. (15° C.) under N₂ atmosphere. The mixturewas stirred at R.T. for 12 h. MeOH (20 mL) was added. The mixture wasfiltered, and the filtrate was concentrated to dryness. The residue wasdissolved in EA (80 mL). The solution was washed with brine, dried overanhydrous Na₂SO₄ and concentrated at low pressure. The residue waspurified on a silica gel column (5% MeOH in DCM) to give AA-5 (1.4 g,crude) as a white solid.

Preparation of (AA):

AA-5 (2.40 g, 2.60 mmol) was dissolved in TBAF (10 mL, 1M in THF). Themixture was stirred at R.T. (15° C.) for 30 mins. The mixture wasconcentrated to dryness, and the residue was dissolved in EA (60 mL).The solution was washed with brine, dried over MgSO₄ and concentratedunder reduced pressure. The residue was purified on a silica gel column(5% MeOH in DCM) to give AA (1.50 g, 95.8%) as a white solid. ESI-MS:m/z 625.3 [M+Na]⁺.

Preparation of (14-1):

To a solution of AA (60.0 mg, 99.57 μmol, 1.00 eq.) in pyridine (1 mL)was added isobutyric anhydride (31.50 mg, 199.13 μmol, 2.00 eq.) in 1portion at R.T. (15° C.) under N₂ atmosphere. The mixture was stirred atR.T. for 12 h. The mixture was concentrated, and the residue waspartitioned between EA and water. The combined organic phases werewashed with water and brine, and dried over anhydrous Na₂SO₄. Themixture was filtered, and the filtrate was concentrated to dryness. Theresidue was purified by silica gel chromatography (30% EA in PE) toafford 14-1 (59.00 mg, 79.77%) as a white solid.

Preparation of (14A):

14-1 (57.00 mg, 76.74 μmol, 1.00 eq.) was dissolved in 80% CH₃COOH (8mL). The solution was stirred at R.T. (15° C.) for 12 h. The mixture wasconcentrated to dryness. The residue was purified on a silica gel column(2.5% MeOH in DCM) to give 14A (23.00 mg, 68.05%) as a white foam.ESI-MS: m/z 441.2 [M+H]⁺, 463.2 [M+Na]⁺.

Example 4 Preparation of Compound 15A

Preparation of (15-1):

15-1 was prepared in similar manner as 14-1 using AA (60.00 mg, 99.57μma 1.00 eq.) in pyridine (1 mL) and propionic anhydride (25.92 mg,199.13 μmol, 2.00 eq.). 15-1 (white solid, 56.00 mg, 78.69%).

Preparation of (15A):

Compound 15A was prepared in similar manner as 14A using 15-1 (54.00 mg,75.55 μmol, 1.00 eq.) 15A (white foam, 18.00 mg, 57.78%). ESI-MS: m/z413.1 [M+H]⁺.

Example 5 Preparation of Compound 16A

Preparation of (16-1):

16-1 was prepared in similar manner as 14-1 using AA (62.00 mg, 102.89μmol, 1.00 eq.) in pyridine (1 mL) and pentanoic anhydride (38.32 mg,205.77 μmol, 2.00 eq.). 16-1 (white solid, 60.00 mg, 75.65%).

Preparation of (16A):

Compound 16A was prepared in similar manner as 14A using 16-1 (75.00 mg,97.30 μmol, 1.00 eq.) 16A (white foam, 28.00 mg, 61.43%). ESI-MS: m/z469.2 [M+H]⁺.

Example 6 Preparation of Compound 24A

Preparation of (24-1):

To a stirred solution of AA-1 (300.0 mg, 497.83 μmol) in anhydrouspyridine (0.5 mL) was added DMTrCl (337.36 mg, 995.66 μmol) at R.T. (17°C.) under N₂ atmosphere. The solution was stirred at 50° C.-60° C. for12 h. The mixture was concentrated to dryness under reduced pressure,and the residue was dissolved in EA (40 mL). The solution was washedwith brine, dried over anhydrous MgSO₄, and concentrated to dryness atlow pressure. The residue was purified on a silica gel column using 20%EA in PE to give 24-1 (300 mg, 66.59%) as a white solid.

Preparation of (24-2):

To a stirred solution of 24-1 (100.00 mg, 110.50 μmol) in anhydrouspyridine (0.5 mL) was added DMAP (6.75 mg, 55.25 mol), DCC (22.80 mg,110.50 μmol) and n-actanoic acid (31.87 mg, 221.00 μmol) at R.T. (18°C.) under N₂ atmosphere. The solution was stirred at R.T. for 12 h. Thesolution was concentrated to dryness under reduced pressure. The residuewas purified on a silica gel column using 15% EA in PE to give 24-2(98.00 mg, 86.0%) as a white foam.

Preparation of (24A):

24-2 (90.00 mg, 87.28 μmol) was dissolved in 80% CH₃COOH (20 mL) at R.T.(16° C.). The mixture was stirred R.T. for 12 h. The reaction wasquenched with MeOH, and the mixture was concentrated to dryness. Theresidue was purified on a silica gel column (5% MeOH in DCM) to give 24A(33.00 mg, 88.7%) as a white solid. ESI-MS: m/z 427.2 [M=H]⁺.

Example 7 Preparation of Compound 25A

Preparation of (BB-2):

To a stirred solution of BB-1 (500.00 mg, 0.87 mmol) in anhydrouspyridine (1 mL) was added TBSCl (236.5 mg, 1.57 mmol) at 20° C. underN₂. The solution was stirred at 50° C.-60° C. for 12 h. The solution wasconcentrated to dryness under reduced pressure. The residue wasdissolved in EA (50 mL). The solution was washed with sat. NaHCO₃solution and brine, and dried over anhydrous MgSO₄. The solution wasfiltered, and the filtrate was concentrated to dryness. The residue waspurified on a silica gel column to give BB-2 (510.00 mg, 85.06%) as awhite solid.

Preparation of (BB-3):

To a stirred solution of BB-2 (430.00 mg, 625.15 mmol) in anhydrous MeCN(6 mL) was added TPSCl (368.65 mg, 1.25 mmol), DMAP (152.75 mg, 1.25mmol) and TEA (126.52 mg, 1.25 mmol) at R.T. The mixture was stirred for2 h. NH₄OH (8 mL) was added, and the mixture stirred for 3 h. Themixture was extracted with EA (3×40 mL). The organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified on a silica gel column (25% EA in PE)to give BB-3 (500 mg of crude) as a yellow foam.

Preparation of (BB-4):

To a stirred solution of BB-3 (500 mg of crude, 0.72 mmol) in anhydrousDCM (7 mL) was added DMTrCl (365 mg, 1.0 mmol) and collidine (305 mg,2.5 mmol) and AgNO₃ (184 mg, 1.08 mmol) at R.T. (15° C.) under N₂atmosphere. The mixture was stirred at R.T. for 12 h. MeOH (5 mL) wasadded. The mixture was filtered, and the filtrate was concentrated todryness. The residue was dissolved in EA (50 mL). The solution waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated at lowpressure. The residue was purified on a silica gel column (5% MeOH inDCM) to give BB-4 (500 mg, 70.3%) as a white solid.

Preparation of (BB):

BB-4 (1.00 g, 1.01 mmol) was dissolved in TBAF (5 mL, 1M in THF) andstirred at R.T. for 30 mins. The mixture was diluted with EA (100 mL).The mixture was washed with water and brine, and dried over anhydrousMgSO₄. The organic phase was concentrated to dryness. The residue waspurified on the silica gel column (30% EA in PE) to give BB (0.80 g,91.5%) as a white solid. ESI-MS: m/z 873.7 [M+1]⁺.

Preparation of (25-1):

To a solution of BB (100.00 mg, 114.29 μmol) in anhydrous pyridine (1.5mL) was added DMAP (2.79 mg, 22.86 mol), DCC (70.75 mg, 342.88 μmol) andn-octanoic acid (49.45 mg, 342.88 μmol) at R.T. (18° C.) under N₂atmosphere. The solution was stirred at R.T. for 12 h. The solution wasconcentrated to dryness under reduced pressure. The residue was purifiedon a silica gel column using 15% EA in PE to give 25-1 (95.00 mg,83.03%) as a white foam.

Preparation of (25A):

25-1 (110.00 mg, 109.87 μmol) was dissolved in 80% CH₃COOH (25 mL) atR.T. (15° C.). The mixture was stirred for 12 h. The reaction wasquenched with MeOH, and the solution was concentrated to dryness. Theresidue was purified on a silica gel column (5% MeOH in DCM) to give 25A(30.00 mg, 64.03%) as a white solid. ESI-MS: m/z 427.2 [M+H]⁺.

Example 8 Preparation of Compound 26A

Preparation of (26-1):

To a solution of N-Boc-L-Valine (620.78 mg, 2.86 mmol) and TEA (144.57mg, 1.43 mmol) in anhydrous THF (2.5 mL) was added BB (250.00 mg, 285.73μmol). The mixture was co-evaporated with pyridine and toluene to removewater. The residue was dissolved in THF (2.5 mL). DIPEA (369.28 mg, 2.86mmol) was added, followed by addition of BOP—C₁ (363.68 mg, 1.43 mmol)and 3-nitro-1H-1,2,4-triazole (162.95 mg, 1.43 mmol) at R.T. (18° C.).The mixture was stirred at R.T. for 12 h and then diluted with EA (40mL). The solution was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to dryness at low pressure. The residue was purified on asilica gel column (30% EA in PE) to give 26-1 (220 mg, crude) as a whitefoam.

Preparation of (26-2):

26-1 (250.0 mg, 232.73 μmol) was dissolved in 80% CH₃COOH (30 mL). Thesolution was heated to 50° C. and stirred for 12 h. The reaction wasquenched with MeOH, and the solution was concentrated to dryness. Theresidue was purified on a silica gel column (5% MeOH in DCM) to give26-2 (80.00 mg, 68.82%) as a white foam.

Preparation of (26A):

26-2 (78.00 mg, 156.16 μmol) was dissolved in HCl/dioxane (1.5 mL) andEA (1.5 mL) at R.T. (19° C.). The mixture was stirred at R.T. for 30mins. The solution was concentrated to dryness at low pressure Theresidue was purified by prep-HPLC to give 26A (23 mg, 31.25%) as a whitesolid. ESI-MS: m/z 400.20 [M+H]⁺, 799.36 [2M+H]⁺.

Example 9 Preparation of Compound 27A

Preparation of (27-1):

27-1 was prepared in similar manner as 26-1 using BB (250.0 mg, 276.25μmol), (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (360.11mg, 1.66 mmol) and TEA (83.86 mg, 828.75 μmol). 27-1 (white foam, 220.0mg, 72.12%).

Preparation of (27-2):

27-2 was prepared in similar manner as 26-2 using 27-1 (230.00 mg,208.29 μmol, 1.00 eq.). 27-2 (white foam, 80.00 mg, 77.66%).

Preparation of (27A):

27A was prepared in similar manner as 26 using 27-2 (100.00 mg, 200.20μmol, 1.00 eq.). 27A (white solid, 56 mg, 59.57%). ESI-MS: m/z 400.0[M+H]⁺, 422.1 [M+Na]⁺; 799.1 [2M+H]⁺, 821.2 [2M+Na]⁺.

Example 10 Preparation of Compound 13A

Preparation of (13-1):

To a solution of 2A (200 mg, 0.67 mmol) in anhydrous pyridine (5 mL) wasadded TBSCl (120 mg, 0.8 mmol) at R.T. The mixture was stirredovernight, and the reaction mixture was diluted with EA. The mixture waswashed with NaHCO₃ aq. solution and brine. The organic layer was dried,filtered and concentrated to give residue, which was purified by silicagel column chromatography (5% MeOH in DCM to 25% MeOH in DCM to give13-1 (153 mg, 55%) as a white solid.

Preparation of (13-2):

To a solution of 13-1 (54 mg, 0.13 mmol) in anhydrous DCM (2 mL) wasadded collidine (95 μL, 0.78 mmol), DMTrCl (262 mg, 0.78 mmol) and AgNO₃(66 mg, 0.39 mmol) at R.T. The mixture was stirred overnight, and thendiluted with DCM (5 mL). The mixture was filtered through a pre-packedcelite funnel, and the filtrate was washed with NaHCO₃ aq. solution, 1.0M citric acid solution and then brine. The organic layer was dried overNa₂SO₄, and concentrated at low pressure to give a residue. The residuewas purified by silica gel column chromatography (25% EA in PE to 100%EA) to give 13-2 (83.5 mg, 63.6%).

Preparation of (13-3):

To a solution of 13-2 (83 mg, 0.081 mmol) in THF (1 mL), was added a 1Msolution of TBAF in THF (0.122 mL, 0.122 mmol) at ice bath temperature.The mixture was stirred for 1.5 h. The mixture was diluted with EA, andwashed with water and brine. The organic layer was dried andconcentrated to give the crude product, which was purified by silica gelcolumn chromatography (DCM to 5% MeOH in DCM) to give 13-3 (66.6 mg,91%) as a white foam.

Preparation of (13-4):

13-3 (66.6 mg, 0.074 mmol) was co-evaporated with toluene and THF (3×).Bis(POC)phosphate (33 mg, 0.96 mmol) was added, and then co-evaporatedwith toluene (3×). The mixture was dissolved in anhydrous THF (1.5 mL)and cooled in an ice bath (0 to 5° C.). 3-nitro-1,2,4-triazole (13 mg,0.11 mmol), diisopropylethyl amine (54 μL, 0.3 mmol), and BOP—C₁ (28 mg,0.11 mmol) were added successively. The mixture was stirred 2 h at 0 to5° C., diluted with EtOAc, washed with 1.0M citric acid, sat. aq. NaHCO₃and brine, and dried with Na₂SO₄. The residue was purified on silica (10g column) with CH₂Cl₂:i-PrOH (4-10% gradient) to give 13-4 (68 mg, 76%)as a white solid.

Preparation of (13A):

13-4 (68 mg, 0.07 mmol) was dissolved in 80% HCOOH. The mixture wasstirred at R.T. for 2 h. The solvents were evaporated at R.T. andco-evaporated with toluene (3×). The residue was dissolved in 50%CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) using CH₃CN andH₂O. The product was lyophilization to give 13A (4.8 mg, 14%) as a whitefoam. ESI-LCMS: m/z=613.1 [M+H]⁺, 1225.2 [2M+H]⁺.

Example 11 Preparation of Compound 17A

Preparation of (17-1):

17-1 (40.7 mg, 53%) was prepared in the same manner from 1-7 (50 mg,0.087 mmol) and bis(isopropyloxycarbonyloxymethyl)phosphate (58 mg,0.175 mmol) with DIPEA (75 μL, 0.52 mmol), BOP—C₁ (66.2 mg, 0.26 mmol),and 3-nitro-1,2,4-triazole (30 mg, 0.26 mmol) in THF (0.4 mL) in asimilar manner as 13-4.

Preparation of (17A):

17-1 (40 mg, 0.045 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and4N HCl in dioxane (34 μL, 0.135 mmol) was added at 0 to 5° C. Themixture was stirred at R.T. for 3 h. Anhydrous EtOH (200 μL) was added.The solvents were evaporated at R.T. and co-evaporated with toluene(3×). The residue was purified on silica (10 g column) with MeOH/CH₂Cl₂(5-7% gradient) and lypholized give 17A (15.4 mg, 76%) as a white foam.ESI-LCMS: m/z=614.15 [M+H]⁺, 1227.2 [2M+H]⁺.

Example 12 Preparation of Compound 18A

Preparation of (18-1):

To a stirred solution of 1-7 (80 mg, 0.14 mmol) in anhydrous CH₃CN (2.0mL) was added N-methylimidazole (0.092 mL, 1.12 mmol) at 0° C.(ice/water bath). A solution of phenyl (isopropoxy-L-alaninyl)phosphorochloridate (128 mg, 0.42 mmol, dissolved in CH₃CN (0.5 mL)) wasthen added (prepared according to a general procedure as described inMcGuigan et al., J. Med. Chem. (2008) 51:5807-5812). The solution wasstirred at 0 to 5° C. for h and then stirred at R.T. for 16 h. Themixture was cooled to 0 to 5° C., diluted with EA followed by theaddition of water (5 mL). The solution was washed with 1.0M citric acid,sat. aq. NaHCO₃ and brine, and dried with MgSO₄. The residue waspurified on silica (10 g column) with EA/hexanes (25-100% gradient) togive 18-1 (57.3 mg, 49%) as a foam.

Preparation of (18A):

18-1 (57.3 mg, 0.07 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and4N HCl in dioxane (68 μL, 0.27 mmol) was added at 0 to 5° C. The mixturewas stirred at R.T. for 2 h, and anhydrous EtOH (100 μL) was added. Thesolvents were evaporated at R.T. and co-evaporated with toluene (3×).The residue was purified on silica (10 g column) with MeOH/CH₂Cl₂ (1-7%gradient) and lypholized to give 18A (27.8 mg, 72%) as a white foam.ESI-LCMS: m/z=571.1 [M+H]⁺, 1141.2 [2M+H]⁺.

Example 13 Preparation of Compound 28A

Preparation of (28-1):

28-1 (68.4 mg, 44.7%) was prepared from 1-7 (100 mg, 0.174 mmol) andbis(tert-butoxycarbonyloxymethyl)phosphate (126 mg, 0.35 mmol) withDIPEA (192 μL, 1.04 mmol), BOP—C₁ (133 mg, 0.52 mmol), and3-nitro-1,2,4-triazole (59 mg, 0.52 mmol) in THF (1.5 mL) in the samemanner as 13-4.

Preparation of (28A):

28A (31.4 mg, 67%) was prepared from 28-1 (68 mg, 0.077 mmol) in thesame manner as 17A. ESI-LCMS: m/z=627.15 [M+Na]⁺, 1219.25 [2M+H]⁺.

Example 14 Preparation of Compound 19A

Preparation of (19-1):

To a solution of 1-7 (100 mg, 0.175 mmol) in anhydrous CH₃CN (2 mL) wasadded 5-ethylthio-1H-tetrazole in CH₃CN (0.25M; 0.84 mL, 0.21 mmol).Bis-SATE-phosphoramidate (95 mg, 0.21 mmol) in CH₃CN (1 mL) was added at0 to 5° C. dropwise. The mixture was stirred 2 h at 0 to 5° C. under Ar.A solution of 77% m-CPBA (78 mg, 0.35 mmol) in DCM (1 mL) was added, andthe mixture stirred 2 h at 0 to 5° C. under Ar. The mixture was dilutedwith EtOAc (50 mL), washed with 1.0M citric acid, sat. NaHCO₃ and brine,and dried with MgSO₄. The mixture was filtered, and the solvents wereevaporated in vacuo. The residue was purified on silica (10 g column)with EA/hexanes (20-100% gradient) to give 19-1 (105 mg, 63.6%) as awhite foam.

Preparation of (19A):

19-1 (105 mg, 0.112 mmol) was dissolved in anhydrous CH₃CN (0.8 mL), and4N HCl in dioxane (84 μL, 0.334 mmol) was added at 0 to 5° C. Themixture was stirred at R.T. for 2 h. Anhydrous EtOH (100 μL) was added.The solvents were evaporated at R.T., and co-evaporated with toluene(3×). The residue was purified on silica (10 g column) with MeOH/CH₂Cl₂(1-7% gradient) and lypholized to give 19A (42.7 mg, 57%) as a whitefoam. ESI-LCMS: m/z=692.15 [M+Na]⁺, 1339.30 [2M+H]⁺.

Example 15 Preparation of Compound 20A

Preparation of (20-2):

1-7 (100 mg, 0.174 mmol) was co-evaporated with anhydrous pyridine (3×),toluene (3×) and CH₃CN (3×), and dried under high vacuum overnight. 1-7was dissolved in CH₃CN (2 mL). A proton sponge (112 mg, 0.52 mmol),POCl₃ (49 uL, 0.52 mmol) were added at 0 to 5° C. The mixture wasstirred for 3 h at 0 to 5° C. to give intermediate 20-1. To thissolution, L-alanine isopropyl ester hydrochloride (146 mg, 0.87 mmol),and TEA (114 uL, 1.74 mmol) were added. The mixture was stirred for 4 hat 0 to 5° C. The mixture was stirred 2 h at 0 to 5° C., then dilutedwith EtOAc. The mixture was washed with 1.0M citric acid, sat. aq.NaHCO₃ and brine, and dried with Na₂SO₄. The residue was purified onsilica (10 g column) with CH₂Cl₂/MeOH (0-7% gradient) to give 20-2 (67mg, 43.7%) as a white solid.

Preparation of (20A):

20-2 (65 mg, 0.074 mmol) was dissolved in anhydrous CH₃CN (0.5 mL), and4N HCl in dioxane (55 μL, 0.22 mmol) was added at 0 to 5° C. The mixturewas stirred at R.T. for 1.5 h. A second portion of 4N HCl in dioxane (15μL) was added, and the mixture stirred at R.T. for 2 h. Anhydrous EtOH(300 μL) was added. The solvents were evaporated at R.T. andco-evaporated with toluene (3×). The residue was dissolved in 50%CH₃CN/H₂O, was purified on a reverse-phase HPLC (C18) with CH₃CN andwater, and lyophilized to give 20A (9 mg, 20%) as a white foam.ESI-LCMS: m/z=608.15 [M+H]⁺, 1215.3 [2M+H]⁺.

Example 16 Preparation of Compound 23A

Preparation of (23-2):

To a stirred solution of 1-7 (100 mg, 0.175 mmol) in anhydrous CH₃CN(2.0 mL) was added N-methylimidazole (0.14 mL, 1.4 mmol) at 0° C.(ice/water bath). A solution of 23-1 (220 mg, 0.53 mmol, dissolved in0.5 mL of CH₃CN), (prepared according to a general procedure describedin Bondada, L. et al., ACS Medicinal Chemistry Letters, (2013)4(8):747-751) was added. The solution was stirred at 0 to 5° C. for 1 hand then stirred at R.T. for 16 h. The mixture was cooled to 0 to 5° C.,diluted with EA followed by addition of water (5 mL). The solution waswashed with 1.0M citric acid, sat. aq. NaHCO₃ and brine, and dried withMgSO₄. The residue was purified on silica (10 g column) with EA/hexanes(25-100% gradient) to give 23-2 (56.4 mg, 33.7%) as a white foam.

Preparation of (23A):

23-2 (56 mg, 0.0585 mmol) was dissolved in anhydrous CH₃CN (0.7 mL), and4N HCl in dioxane (44 μL, 0.176 mmol) was added at 0 to 5° C. Themixture was stirred at R.T. for 2 h. 4N HCl in dioxane (20 μL) wasadded. The mixture was stirred at R.T. for 2 h. Anhydrous EtOH (100 μL)was added. The solvents were evaporated at R.T. and co-evaporated withtoluene (3×). The residue was purified on silica (10 g column) withMeOH/CH₂Cl₂ (1-7% gradient) and lypholized to give 23A (27.6 mg, 69%) asa white foam. ESI-LCMS: m/z=685.2 [M+H]⁺.

Example 17 Preparation of Compound 29A

Preparation of (29-1):

To a solution of BB (100 mg, 0.114 mmol) in anhydrous CH₃CN (2 mL) wereadded a solution of bis-SATE-phosphoramidate (62.2 mg, 0.14 mmol) inCH₃CN (1 mL) followed by 5-ethylthio-1H-tetrazole in CH₃CN (0.25M; 0.56mL, 0.14 mmol) at 0 to 5° C. dropwise. The mixture was stirred 2 h at 0to 5° C. under Ar. A solution of 77% m-CPBA (49 mg, 0.22 mmol) in DCM (1mL) was added, and the mixture was stirred 2 h at 0 to 5° C. under Ar.The mixture was diluted with EtOAc (50 mL), washed with 1.0M citricacid, sat. NaHCO₃, and brine, and dried with MgSO₄. The mixture wasfiltered and the solvents were evaporated in vacuo. The residue waspurified on silica (10 g column) with EA/hexanes (10-100% gradient) togive 29-1 (72 mg, 50.8%) as a white solid.

Preparation of (29A):

29-1 (72 mg, 0.056 mmol) was dissolved in anhydrous CH₃CN (1.0 mL), and4N HCl in dioxane (87 μL, 0.35 mmol) was added at 0 to 5° C. The mixturewas stirred at R.T. for 2 h. Intermediate 29-2 was observed by LCMS. Thesolvents were evaporated at R.T. and co-evaporated with toluene (3×).The residue obtained was re-dissolved in 80% HCOOH (2 mL). The mixturewas stirred at R.T. for 4.5 h. The solvents were evaporated at R.T. andco-evaporated with toluene (3×). Anhydrous EtOH (3×5 mL) was added. Theresidue was dissolved in 50% CH₃CN/H₂O, purified on a reverse-phase HPLC(C18) using CH₃CN and H₂O, and lyophilized to give 29A (19.2 mg) as awhite foam. ESI-LCMS: m/z=669.2 [M+H]⁺, 1337.25 [2M+H]⁺.

Example 18 Preparation of Compound 30A

Preparation of (30-1):

30-1 (98 mg, 72.6%) was prepared in the same manner from BB (100 mg,0.114 mmol) and bis(tert-butoxycarbonyloxymethyl)phosphate (83 mg, 0.35mmol) with DIPEA (126 μL, 0.69 mmol), BOP—C₁ (87 mg, 0.34 mmol), and3-nitro-1,2,4-triazole (39 mg, 0.34 mmol) in THF (1.5 mL) in the samemanner as 13-4.

Preparation of (30A):

30A (30.2 mg, 60%) was prepared from 30-1 (98 mg, 0.083 mmol) in thesame manner as 17A. ESI-LCMS: m/z=609.15 [M+H]⁺, 1217.3 [2M+H]⁺.

Example 19 Preparation of Compound 21A

Preparation of (21-3):

A solution of 21-1 (4.7 g, 11.2 mmol; prepared according to theprocedure Villard et al., Bioorg. Med. Chem. (2008) 16:7321-7329) andEt₃N (3.4 mL, 24.2 mmol) in THF (25 mL) was added dropwise over 1 h to astirred solution of N,N-diisopropylphosphorodichloridite (1.0 mL, 5.5mmol) in THF (35 mL) at −75° C. The mixture was stirred at R.T. for 4 h.The mixture was filtered, and the filtrate concentrated. The oilyresidue was purified on silica gel column with EtOAc/hexanes (2-20%gradient) to give 21-3 (1.4 g, 26%).

Preparation of (21-4):

To a solution of 21-2 (50 mg, 0.08 mmol) and 21-3 (110 mg, 0.11 mmol) inCH₃CN (1.0 mL) was added 5-(ethylthio)tetrazole (0.75 mL, 0.16 mmol;0.25 M in CH₃CN). The mixture was stirred at R.T. for 1 h. The mixturewas cooled to −40° C., and a solution of 3-chloroperoxybenzoic acid (37mg, 0.16 mmol) in CH₂Cl₂ (0.3 mL) was added. The mixture was warmed toR.T. over 1 h. The reaction was quenched with 7% Na₂S₂O₃ solution in sataq. NaHCO₃. The mixture was diluted with EtOAc, and the layers wereseparated. The organic layer was washed with brine and dried withNa₂SO₄. The solvent was evaporated, and the residue was purified on asilica gel column with EtOAc/hexanes (30-100% gradient) to give 21-4 (52mg, 45%).

Preparation of (21A):

A solution of 21-4 (52 mg, 0.036 mmol) in MeCN (0.5 mL) and HCl (45 μL;4 N in dioxane) was stirred 20 h at R.T. The reaction was quenched withMeOH, and the solvents were evaporated. The residue was co-evaporatedwith toluene and purified on a silica gel column with MeOH/CH₂Cl₂ (4-10%gradient) to give 21A (14 mg, 51%). ESI-LCMS: m/z=702 [M+H]⁺.

Example 20 Preparation of Compound 22A

Preparation of (22-2):

A mixture of 22-1 (0.14 g, 0.24 mmol; prepared according to theprocedure described in WO 2008/082601, filed Dec. 28, 2007) and 21-2(120 mg, 0.2 mmol) was rendered anhydrous by evaporating with pyridineand then dissolved in pyridine (3 mL). Pivaloyl chloride (48 μL) wasadded dropwise at −15° C. The mixture was stirred at −15° C. for 2 h.The reaction was quenched with sat. aq. NH₄Cl solution and diluted withCH₂Cl₂. The organic layer was washed with brine and dried with Na₂SO₄.The solvents were evaporated, and the residue was purified on a silicagel column with EtOAc/hexanes (30-100% gradient) to give 22-2 (50 mg,24%).

Preparation of (22-3):

A mixture of 22-2 (43 mg; 0.04 mmol) in CCl₄ (0.8 mL), L-valineisopropyl ester hydrochloride (20 mg, 0.12 mmol) and Et₃N (33 μl, 0.24mmol) was stirred at R.T. for 2 h. The mixture was diluted with EtOAc.The mixture was washed with sat. aq. NaHCO₃ and brine, and dried withNa₂SO₄. The solvents were evaporated, and the residue was purified on asilica gel column with i-PrOH/CH₂Cl₂ (2-10% gradient) to 22-3 (35 mg,75%).

Preparation of (22A):

A solution of 22-3 (35 mg, 0.03 mmol) in MeCN (0.4 mL) and HCl (40 μL; 4N in dioxane) was stirred 4 h at R.T. The reaction was quenched with theaddition of MeOH, and the solvents were evaporated. The residue wasco-evaporated with toluene and purified on a silica gel column withMeOH/CH₂Cl₂ (4-10% gradient) to give 23A (11 mg, 56%). ESI-LCMS: m/z=655[M+H]⁺.

Example 21 Preparation of Compound 7A

Preparation of (7-2):

To a solution of 7-1 (20.0 g, 70.1 mmol) in anhydrous pyridine (230 mL)was added imidazole (19.1 g, 280.7 mmol) and TBSCl (42.1 g, 280.7 mmol)at 25° C. The solution was stirred at 25° C. for 15 h. The mixture wasconcentrated to dryness under reduced pressure, and the residue wasdissolved in EA. A white solid was obtained and filtered. The filtercake was concentrated to dryness to give 7-2 (30.1 g, 83%) as a whitesolid.

Preparation of (7-3):

7-2 (30.1 g, 58.7 mmol) was dissolved in THF (120 mL) and H₂O (80 mL).HOAc (260 mL) was added, and was then stirred at 80° C. for 13 h. Themixture was cooled to R.T., and concentrated to dryness under reducedpressure. The residue was dissolved in EA and filtered. The filter cakewas concentrated to dryness to give 7-3 (20.1 g, 86%) as a white solid.

Preparation of (7-4):

7-3 (20.1 g, 50.4 mmol) was dissolved in anhydrous pyridine (200 mL).Ac₂O (7.7 g, 75.5 mmol) was added and then stirred at 25° C. for 18 h.MMTrCl (46.5 g, 151.1 mmol) and AgNO₃ (25.5 g, 151.1 mmol) were added.The solution was stirred at 25° C. for 15 h. The reaction was quenchedwith water. The mixture was concentrated to dryness under reducedpressure, and the residue was dissolved in EA. The solution was washedwith brine. The organic layer was dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuum to dryness. The residue was purifiedon silica gel column (2% MeOH in DCM) to give 7-4 (21.5 g, 60%) as awhite foam.

Preparation of (7-5):

7-4 (4.3 g, 6.0 mmol) was dissolved in NH₃/MeOH (40 mL). The mixture wasstirred at 25° C. for 20 h. The solution was evaporated to dryness. Theresidue was purified on silica gel column (2% MeOH in DCM) to give 7-5(3.1 g, 76.5%) as a yellow solid.

Preparation of (7-6):

To a solution of 7-5 (3.1 g, 4.6 mmol) in anhydrous DCM (50 mL) wasadded Dess-Martin reagent (3.5 g, 8.2 mmol) at 0° C. The mixture wasstirred at 0° C. for 2 h, and then stirred at R.T. for 2 h. The reactionwas quenched with saturated NaHCO₃ and Na₂S₂O₃ solution. The organiclayer was washed with brine (2×) and dried over anhydrous Na₂SO₄. Thesolvent was evaporated to give crude 7-6 (2.8 g) as a yellow foam.

Preparation of (7-7):

To a solution of 7-6 (2.8 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added37% HCHO (2.7 g, 33.5 mmol) and 2.0 N NaOH aqueous solution (3.0 mL, 6.0mmol). The mixture was stirred for 12 h at 25° C. The mixture wastreated with EtOH (20 mL) and NaBH₄ (2.5 g, 66.9 mmol) and stirred for30 mins. The reaction was quenched with sat. aq. NH₄Cl and extractedwith EA (50 mL). The organic layer was dried over Na₂SO₄. Theconcentrated organic phase was purified on silica gel column (2% MeOH inDCM) to give 7-7 (2.1 g, 72.4%) as a yellow solid.

Preparation of (7-8):

To a solution of 7-7 (2.1 g, 3.0 mmol) in DCM (20 mL) was added pyridine(5 mL) and DMTrCl (1.0 g, 3.0 mmol) at 0° C. The solution was stirred at25° C. for 1 h. The mixture was treated with MeOH (8 mL), andconcentrated under reduced pressure. The residue was purified on silicagel column (2% MeOH in DCM) to give 7-8 (1.1 g, 36.7%) as a yellowsolid.

Preparation of (7-9):

To a solution of 7-8 (1.1 g, 1.1 mmol) in anhydrous pyridine (10 mL) wasadded TBDPSCl (0.9 g, 3.3 mmol) and AgNO₃ (0.6 g, 3.3 mmol). The mixturewas stirred at 25° C. for 15 h. The solid was removed by filtration, andthe filtrate was concentrated at low pressure. The residue was dissolvedin EA. The resulting solution was washed with brine. The organic layerwas dried over Na₂SO₄ and concentrated at low pressure. The residue waspurified by column chromatography (2% MeOH in DCM) to give 7-9 (1.2 g,88.2%) as a white foam.

Preparation of (7-10):

To a solution of 7-9 (1.2 g, 1.0 mmol) in anhydrous DCM (15 mL) wasadded Cl₂CHCOOH (0.6 mL) at −78° C. The mixture was stirred at −20° C.for 1 h. The reaction was quenched with sat. aq. NaHCO₃ and extractedwith DCM. The organic layer was dried over Na₂SO₄ and concentrated atlow pressure. The residue was purified on silica gel column (2% MeOH inDCM) to give 7-10 (693 mg, 76.3%) as a white foam.

Preparation of (7-11):

To a solution of 7-10 (693 mg, 0.74 mmol) in anhydrous DCM (25 mL) andpyridine (291 mg, 3.70 mmol) was added Tf₂O (312 mg, 1.1 mmol) in DCM (1mL) dropwise at 0° C. The mixture was stirred at 0° C. for 15 mins. Thereaction was quenched with ice water. The organic layer was separatedand washed with brine. The organic layer was dried over anhydrous Na₂SO₄and evaporated to give 7-11 (442 mg, crude) as a yellow foam.

Preparation of (7-12):

To a solution of 7-11 (442 mg, 0.41 mmol) in anhydrous DMF (5 mL) wasadded NaN₃ (134 mg, 2.1 mmol). The mixture was stirred at R.T. for 12 h.The reaction was quenched with water and extracted with EA (20 mL, 2×).The organic layer were washed with brine, dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified on a silicagel column (1% MeOH in DCM) to give pure 7-12 (313 mg, 78.6%) as a whitefoam.

Preparation of (7-13):

A mixture of 7-12 (313 mg, 0.32 mmol) and NH₄F (240 mg, 6.5 mmol) inMeOH (10 mL) was stirred at 80° C. for 12 h. The mixture was cooled downto R.T. The solid was removed by filtration. The solvent was removedunder reduced pressure, and the residue was purified on a silica gelcolumn (5% MeOH in DCM) to give 7-13 (102 mg, 52%) as a white foam.

Preparation of (7A):

7-13 (102 mg, 0.17 mmol) was dissolved in CH₃COOH (80%). The mixture wasstirred at 60° C. for 2 h and then cooled to R.T. The mixture wasconcentrated to dryness under reduced pressure. The residue was purifiedon silica gel column (5% to 10% MeOH in DCM) to give the crude product(67 mg). The crude product was purified by prep-HPLC (0.1% NH₄HCO₃ inwater and CH₃CN) to give 7A (37.5 mg, 66%) as a white solid. MS: m/z341[M+H]⁺.

Example 22 Preparation of Compound 31A

Preparation of (31-2):

To a stirred solution of 7-7 (1.92 g, 27.3 mmol), PPh₃ (1.43 g, 54.7mmol), EtOH (0.25 g, 54.7 mmol) in anhydrous dioxane (20 mL) was addedDIAD (1.11 g, 54.7 mmol) dropwise at 0° C. The solution was stirred at25° C. for 15 h. The reaction was quenched with water and extracted withEA. The mixture was washed with water and brine. The organic layer wasdried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuumto dryness, and the residue was purified on a silica gel column (2% to5% MeOH in DCM) to give 31-1 (1.43 g, 71%) as a white foam.

Preparation of (31-2):

To a stirred solution of 31-1 (1.43 g, 19.6 mmol) in DMF (15 mL) wasadded TEA (0.59 g, 58.8 mmol) and DMTrCl (0.99 g, 29.4 mmol) at 0° C.The solution was stirred at 25° C. for 12 h. The mixture was treatedwith MeOH (1 mL), and diluted with EA. The solution was washed withwater and brine. The organic layer was dried over anhydrous NaSO₄, andconcentrated to dryness. The residue was purified on a silica gel column(2% MeOH in DCM) to give 31-2 (1.13 g, 56%) as a yellow solid.

Preparation of (31-3):

To a stirred solution of 31-2 (1.13 g, 1.1 mmol) in anhydrous pyridine(10 mL) was added TBDPSCl (0.91 g, 3.3 mmol) and AgNO₃ (0.61 g, 3.3mmol). The mixture was stirred at 25° C. for 15 h. The solid was removedby filtration, and the filtrate was diluted with EA (50 mL). Thesolution was washed with brine. The organic layer was dried overanhydrous Na₂SO₄, and concentrated at low pressure. The residue waspurified on a silica gel column (2% MeOH in DCM) to give 31-3 (1.22 g,88%) as a white foam.

Preparation of (31-4):

To a stirred solution of 31-3 (1.22 g, 1.0 mmol) in anhydrous DCM (15mL) was added Cl₂CHCOOH (0.6 mL) at −78° C. The mixture was stirred at−20° C. for 1 h. The reaction was quenched with sat. aq. NaHCO₃ andextracted with DCM. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The residue was purified by columnchromatography (2% MeOH in DCM) to give 31-4 (0.52 g, 56%) as a whitefoam.

Preparation of (31-5):

To a stirred solution of 31-4 (0.52 g, 0.5 mmol) in anhydrous DCM (15mL) and pyridine (0.21 g, 2.5 mmol) was added Tf₂O (0.30 g, 1.0 mmol) inDCM (1 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 15mins. The reaction was quenched with ice water. The organic layer wasseparated and washed with water. The organic layer was dried overanhydrous Na₂SO₄ and concentrated at low pressure to give 31-5 (442 mgcrude) as a yellow foam.

Preparation of (31-6):

To a stirred solution of 31-5 (442 mg, 0.4 mmol) in anhydrous DMF (5 mL)was added NaN₃ (131 mg, 2.0 mmol). The mixture was stirred at RT for 12h. The reaction was quenched with water and extracted by EA (20 Ml, 2×).The organic layer was washed with water and dried over Na₂SO₄. Theorganic phase was evaporated to dryness under reduced pressure. Theresidue was purified on a silica gel column (1% MeOH in DCM) to give31-6 (352 mg, 88%) as a white foam.

Preparation of (31-7):

A mixture of 31-6 (352 mg, 0.35 mmol) and NH₄F (392 mg, 10.6 mmol) inMeOH (10 mL) was stirred at 80° C. for 12 h. The mixture was cooled toR.T. The solid was removed by filtration. The solvent was concentratedunder reduced pressure. The residue was purified on a silica gel column(2% to 5% MeOH in DCM) to give crude 31-7 (151 mg). The crude productwas purified by prep-HPLC (0.1% NH₄HCO₃ in water and CH₃CN) to give 31-7(71.5 mg, 32%) as a white solid. MS: m/z 641 [M+H]⁺.

Preparation of (31-8):

A mixture of 31-7 (64 mg, 0.1 mmol) and bis(pivaloyloxymethyl)phosphate,after rendered anhydrous by evaporating with toluene, was dissolved inCH₃CN (1 mL) and cooled to 0° C. BopCl (40 mg, 0.15 mmol) and NMI (40μL, 0.5 mmol) were added. The mixture was stirred at 0° C. for 2 h.EtOAc was added, and the mixture was washed with 0.5 N aq. citric acid,sat. aq. NaHCO₃ and brine, and then dried with Na₂SO₄. The solvents wereremoved, and the residue was purified on a silica gel column with 3%i-PrOH in CH₂Cl₂ to 31-8 (38 mg, 40%).

Preparation of (31A):

A solution of 31-8 (30 mg, 0.03 mmol) in CH₃CN (0.3 mL) and HCl (30 μL;4 N dioxane) was stirred at R.T. for 100 mins. The reaction was quenchedwith EtOH, and the mixture was evaporated. The crude residue waspurified on a silica gel column with i-PrOH/CH₂Cl₂ (3-10% gradient) toyield 31A (10 mg, 50%). ESI-LCMS: m/z=681 [M+H]⁺.

Example 23 Preparation of Compound 32A

2A (30 mg, 0.1 mmol) was hydrogenated in MeOH over 10% Pd/C at normalpressure. The catalyst was filtered off, and the filtrate was purifiedby RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A lineargradient of MeOH from 0 to 20% in 50 mM triethylammonium acetate buffer(pH 7.5) was used for elution. The corresponding fractions werecombined, concentrated and lyophilized (3×) to remove excess of bufferto yield 32A (17 mg, 63%). ESI-LCMS: m/z=275.2 [M+H]⁺, 297.1 [M+Na]⁺.

Example 24 Preparation of Compound 8A

Preparation of (8-2):

To a solution of 8-1 (3.0 g, 11.15 mmol) in anhydrous pyridine (90 mL)was added imidazole (3.03 g, 44.59 mmol) and TBSCl (6.69 g, 44.59 mmol)at 25° C. under N₂ atmosphere. The solution was stirred at 25° C. for 15h. The solution was concentrated to dryness under reduced pressure. Theresidue was dissolved in EA. The solution was washed with sat. NaHCO₃and brine, and dried over anhydrous MgSO₄. The solvent was removed atlow pressure to give crude 8-2 (4.49 g, 90%) as a white solid.

Preparation of (8-3):

To a stirred solution of 8-2 (3.5 g, 7.04 mmol) in a mixture of EA andEtOH (1:1, 55 mL) was added TsOH (10.7 g, 56.34 mmol) at 0° C. Themixture was stirred at 30° C. for 8 h. Water (30 mL) was added, and thesolution was removed to dryness. The residue was purified on a silicagel column (10% MeOH in DCM) to give 8-3 (1.75 g, 65%) as a white foam.

Preparation of (8-4):

To a solution of 8-3 (3.4 g, 8.88 mmol) in anhydrous pyridine (17 mL)was added collidine (4.3 g, 35.51 mmol), AgNO₃ (5.50 g, 35.51 mmol) andMMTrCl (8.02 g, 26.63 mmol) at 25° C. under N₂. The mixture was stirredat 25° C. for 12 h. MeOH (20 mL) was added, and the solvent was removedto dryness at low pressure. The residue was purified on a silica gelcolumn (10% EA in PE) to give 8-4 (5.76 g, 70%) as a white foam.

Preparation of (8-5):

To a solution of 8-4 (2.0 g, 2.16 mmol) in anhydrous DCM (10 mL) wasadded Cl₂CHCOOH (2.8 g, 21.57 mmol) dropwise at −78° C. The mixture waswarmed to −10° C. and stirred at this temperature for 20 mins. Thereaction was quenched with sat. NaHCO₃ at −10° C. The mixture wasextracted with DCM, washed with brine, and dried over anhydrous MgSO₄.The solution was concentrated at low pressure. The residue was purifiedon silica gel column (10% EA in PE) to give 8-5 (0.99 g, 70%) as a whitefoam.

Preparation of (8-6):

To a stirred solution of 8-5 (3.5 g, 5.34 mmol) in anhydrous DMSO (35mL) was added DCC (3.30 g, 16.03 mmol) and Py.TFA (1.03 g, 5.34 mmol).The mixture was stirred at 30° C. for 1 h. The reaction was quenchedwith cold water at 0° C., and extracted with EA (3×60 mL). Theprecipitate was filtered. The organic layers were washed with brine (3×)and dried over anhydrous MgSO₄. The organic phase was concentrated atlow pressure to give crude 8-6 (3.5 g) as a yellow oil.

Preparation of (8-7):

To a stirred solution of 8-6 (3.5 g, 5.34 mmol) in MeCN (35 mL) wasadded 37% HCHO (11.1 mL) and TEA (4.33 g, 42.7 mmol). The mixture wasstirred at 25° C. for 12 h. The mixture was treated with EtOH (26 mL)and NaBH₄ (3.25 g, 85.5 mmol) and then stirred for 30 mins. The reactionwas quenched with sat. aq. NH₄Cl and extracted with EA (3×60 mL). Theorganic layer was dried over anhydrous MgSO₄, and concentrated at lowpressure. The residue was purified by column chromatography (from 10% EAin PE to 50% DCM in PE) to give 8-7 (1.46 g, 40%) as a white solid.

Preparation of (8-8):

To a stirred solution of 8-7 (1.85 g, 2.7 mmol) in pyridine (24 mL) andDCM (9.6 mL) was added DMTrCl (1.3 g, 3.9 mmol) at −35° C. under N₂atmosphere. The solution was stirred at 25° C. for 16 h. The mixture wastreated with MeOH (15 mL) and concentrated at low pressure. The residuewas purified by column chromatography (EA in PE from 10% to 30%) to give8-8 (1.60 g, 60%) as a white solid.

Preparation of (8-9):

To a solution of 8-8 (1.07 g, 1.08 mmol) in anhydrous pyridine (5 mL)was added AgNO₃ (0.65 g, 3.79 mmol) and TBDPSCl (1.04 g, 3.79 mmol). Themixture was stirred at 25° C. for 16 h. The solvent was removed underreduced pressure. The residue was dissolved in EA (50 mL). The resultingsolution was washed with brine. The organic layer was dried overanhydrous MgSO₄, and concentrated at low pressure. The residue waspurified on a silica gel column (10% EA in PE) to give 8-9 (0.93 g, 70%)as a white foam.

Preparation of (8-10):

To a stirred solution of 8-9 (1 g, 0.82 mmol) in anhydrous DCM (13.43mL) was added Cl₂CHCOOH (2.69 mL) at −78° C. The mixture was stirred at−10° C. for 20 mins. The reaction was quenched with sat. aq. NaHCO₃ andextracted with DCM. The organic layer was dried over anhydrous Na₂SO₄,and concentrated at low pressure. The organic phase was purified bycolumn chromatography (MeOH in DCM form 0.5% to 2%) to give 8-10 (0.48g, 65%) as a solid.

Preparation of (8-11):

To an ice cold solution of 8-10 (0.4 g, 0.433 mmol) in anhydrous DCM(2.7 mL) was added pyridine (171 mg, 2.17 mmol) and Tf₂O (183 mg, 0.65mmol) by dropwise at −35° C. The mixture was stirred at −10° C. for 20mins. The reaction was quenched with ice water and stirred for 30 mins.The mixture was extracted with DCM (3×20 mL). The organic phase waswashed with brine (100 mL), dried over anhydrous Na₂SO₄, andconcentrated at low pressure to give crude 8-11 (0.46 g), which was usedfor next step without further purification.

Preparation of (8-12):

To a solution of 8-11 (0.46 g, 0.43 mmol) in anhydrous DMF (2.5 mL) wasadded NaN₃ (42 mg, 0.65 mmol). The mixture was stirred at 30° C. for 16h. The solution was diluted with water and extracted with EA (3×30 mL).The combined organic layers were dried over anhydrous Na₂SO₄, andconcentrated at low pressure. The residue was purified on a silica gelcolumn (EA in PE from 5% to 15%) to give 8-12 (0.31 g, 70%) as a solid.

Preparation of (8-13):

To a solution of 8-12 (0.31 g, 0.33 mmol) in MeOH (5 mL) was added NH₄F(0.36 g, 9.81 mmol) at 70° C. The mixture was stirred at thistemperature for 24 h. The mixture was evaporated to dryness. The residuewas purified on silica gel column (MeOH in DCM from 0.5% to 2.5%) togive 8-13 (117 mg, 60%) as a white solid.

Preparation of (8A):

8-13 (300 mg, 0.50 mmol) was dissolved in 80% of HOAc (20 mL). Themixture was stirred at 55° C. for 1 h. The reaction was quenched withMeOH and concentrated at low pressure. The residue was purified byprep-HPLC to give 8A (100 mg, 61.3%) as a white solid. ESI-LCMS: m/z325.1 [M+H]⁺.

Example 25 Preparation of Compound 33A

Compound 33-3 was prepared according to the scheme provided above.Compound 33A can be obtained using methods known to those skilled in theart, including those described in U.S. Publication No. 2012/0071434,filed Sep. 19, 2011.

Example 26 Preparation of Triphosphate Compounds

Compounds 3A, 4A, 9A and 11A:

Dry nucleoside (0.05 mmol) was dissolved in a mixture of PO(OMe)₃ (0.7mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15mins at a bath temperature of 42° C., and then cooled down to R.T.N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCl₃ (9μL, 0.11 mmol), and the mixture was kept at R.T. for 40 mins. Thereaction was controlled by LCMS and monitored by the appearance of thecorresponding nucleoside 5′-monophosphate. After more than 50% oftransformation was achieved, tetrabutylammonium salt of pyrophosphate(150 mg) was added, followed by DMF (0.5 mL) to get a homogeneoussolution. After 1.5 hours at ambient temperature, the reaction wasdiluted with water (10 mL) and loaded on the column HiLoad 16/10 with QSepharose High Performance. Separation was done in a linear gradient ofNaCl from 0 to 1N in 50 mM TRIS-buffer (pH7.5). Triphosphate was elutedat 75-80% B. Corresponding fractions were concentrated. Desalting wasachieved by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). Alinear gradient of methanol from 0 to 30% in 50 mM triethylammoniumacetate buffer (pH 7.5) was used for elution. The correspondingfractions were combined, concentrated and lyophilized 3 times to removeexcess of buffer.

Compounds 5A, 6A, 10A and 12A:

Nucleoside 5′-triphosphates with a 4′-azidoalkyl group were dissolved inwater (0.1 mL), methanol (3 mL) was added followed by 10% Pd/C (3 mg).Hydrogen was bubbled through the solution for 2 h. The catalyst wasfiltered off, and the filtrate was purified by RP HPLC on Synergy 4micron Hydro-RP column (Phenominex). A linear gradient of methanol from0 to 20% in 50 mM triethylammonium acetate buffer (pH 7.5) was used forelution. The corresponding fractions were combined, concentrated andlyophilized 3 times to remove excess of buffer.

TABLE 1 Triphosphates obtained from Example 25 ³¹P NMR ³¹P NMR ³¹P NMRMS Compound Pα Pβ Pγ (M-1)

  3A −10.95(d) −23.38(t) −11.97(d) 540.4

  4A −5.36(d) −20.72(t) −11.40(d) 539.3

  5A −6.68 −6.81(d) −22.25(t) −11.79 −11.92(d) 514.0

  6A −5.95 − 6.06(d) −21.38(t) −11.53 −11.65(d) 513

  9A −10.31 −10.44(d) −23.08(t) −11.62 −11.84(d) 579

  10A −9.94 −10.06(d) −23.83(t) −11.77 −11.89(d) 553

  11A −10.79 −10.91(d) −23.24(t) −11.80 −11.92(d) 563.0

  12A −6.48 −6.60(d) −22.13(t) −11.76 −11.88(d) 537.0

Example 27 Additional Compounds

The foregoing syntheses are exemplary and can be used as a startingpoint to prepare a large number of additional compounds. Examples ofcompounds of Formula (I) that can be prepared in various ways, includingthose synthetic schemes shown and described herein, are provided below.Those skilled in the art will be able to recognize modifications of thedisclosed syntheses and to devise routes based on the disclosuresherein; all such modifications and alternate routes are within the scopeof the claims.

Example 28 RSV Assay

The RSV subgenomic replicon 395 HeLa was licensed from Apath (Brooklyn,N.Y.) and was originally developed by Dr. Mark Meeples of Center forVaccines & Immunity, the Research Institute at Nationwide Children'sHospital in Columbus, Ohio. To generate subgenomic RSV replicon, threeglycoprotein genes, those for SH, G, and F, from a full-lengthrecombinant GFP-expressing (rg) RSV antigenomic cDNA were deleted. Intheir place, a blasticidin S deaminase (bsd) gene was inserted. Throughmultiple steps, the RSV replicon was established in HeLa cells. The 395HeLa cells were cultured in Dulbecco's Modified Eagle Medium (DMEM)containing 4500 mg/L D-glucose, L-glutamine, and 110 mg/L sodiumpyruvate (Invitrogen, Cat. #11995-040). The medium was furthersupplemented with 10% (v/v) fetal bovine serum (FBS) (Mediatech, Cat.#35-010-CV), 1% (v/v) penicillin/streptomycin (Mediatech, Cat.#30-002-CI), and 10 μg/mL of Blasticidin (BSD) (Invivogen, Cat. codeant-b1-1). Cells were maintained at 37° C. in a humidified 5% CO₂atmosphere.

Determination of 50% inhibitory concentration (EC₅₀), 90% inhibitoryconcentration (EC₉₀) and 50% cytotoxic concentration (CC₅₀) in RSVreplicon cells were performed by the following procedure. On the firstday, 5000 RSV replicon cells per well were plated in a 96-well plate. Onthe following day, compounds to be tested were solubilized in 100% DMSOto 100× the desired final testing concentration. Each compound wasserially diluted (1:3) up to 9 distinct concentrations. Compounds in100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cellculture media. A 10 μL sample of the compounds diluted to 10% (v/v) DMSOwith cell culture media was used to treat the RSV replicon cells in96-well format. The final DMSO concentration was 1% (v/v). Cells wereincubated with compounds for 7 days at 37° C. in a 5% CO₂ atmosphere. Ineach assay, positive control that was previously characterized in theRSV replicon assay was included.

The Renilla Luciferase Assay System (Promega, Cat. #E2820) was used tomeasure anti-RSV replicon activity. Assay plates were set up as statedabove. Luminescence was recorded using a Perkin Elmer multilabel counterVictor3V. EC₅₀, the concentration of the drug required for reducing RSVreplicon RNA by 50% in relation to the untreated cell control value, wascalculated from the plot of percentage reductions of the optical density(OD) value against the drug concentrations using the Microsoft Excelforecast function.

395 HeLa cell proliferation assay (Promega; CellTiter-Glo® LuminescentCell Viability Assay, Cat. #G7572) was used to measure cell viability.The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneousmethod to determine the number of viable cells in culture based onquantitation of the ATP present, which signals the presence ofmetabolically active cells. Assay plates were set up in the same formatas noted above for the replicon assay. CellTiter-Glo reagent (100 μL)was added to each well and incubated at room temperature for 8 minutes.Luminescence was recorded using a Perkin Elmer multilabel counterVictor3V. The CC₅₀, the concentration of the drug required for reducingviable cells by 50% in relation to the untreated cell control value, wascalculated from the plot of percentage reductions of the luminescencevalue against the drug concentrations using the Microsoft Excel forecastfunction.

Table A1 includes compounds with an EC₅₀ value that is less than 1 TableA2 includes compounds with an EC₅₀ value that is equal to or higher than1 μM and less than 50 μM. Other tested compounds disclosed herein had anEC₅₀ value of 50 μM or greater.

TABLE A1 Compound Compound Compound  2A 14A 16A 13A 15A

TABLE A2 Compound Compound Compound  7A 19A 22A 17A 20A 23A 18A 21A 28A

Standard RSV polymerase assays were conducted in the presence of 3 μLextract of RSV-infected cells in a reaction buffer containing 50 mMtris-acetate pH 8, 120 mM K-acetate, 4.5 mM MgCl₂, 5% glycerol, 2 mMEDTA, 50 ug/mL BSA, and 3 mM DTT. Varying concentration of testcompounds were used to initiate RNA synthesis for 120 mins at 30° C.,and radioactive 33P GTP (15 uCi) was used as tracer. The reaction wasstopped by adding 50 mM EDTA, and RNA samples were purified through G-50size exclusion spin columns and phenol-chloroform extraction. Theradio-labeled RNA products were resolved by electrophoresis on a 6%polyacrylamide TBE gel, and visualized and quantitated after beingexposed on a phosphorlmager screen. Polymerase inhibition experiments(IC50) were conducted the same way in the presence of increasingconcentration of test compounds.

Table A3 includes compounds with an IC50 value that is less than 1 μMagainst the polymerase. Table A4 includes compounds with an IC50 valuethat is equal to or higher than 1 μM and less than 50 μM against thepolymerase. Other tested compounds disclosed herein had an IC50 value of50 μM or greater against the polymerase.

TABLE A3 Compound Compound 3A 11A 4A 12A

TABLE A4 Compound Compound 5A 6A

Example 29 Parainfluenza Virus-3 (PIV-3) Plaque Assay

MA-104 cells were grown in 24-well plates to a confluency of 90% in thepresence of minimal essential medium (MEM) supplemented with 10% fetalbovine serum and antibiotics (C-EMEM). The cells were then washed twicewith non-complete minimal essential medium (NC-EMEM). Test articles weredissolved in DMSO to a stock concentration of 10 mM.

An aliquot of 0.5 mL of the test article at various concentrations wasthen inoculated in triplicate wells and incubated for 60 mins at 37° C.with 5% CO₂ for the diffusion of test article into MA-104 cells. Afterthe incubation period, a stock of human PIV type 3 was thawed anddiluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. Analiquot of 0.1 mL was then inoculated into all the wells except for thenegative and test article toxicity control wells. Upon infection, theplates were incubated for 72 h at 37° C. at 5% CO₂. After incubation,the plates were examined under microscopy to record cytotoxicity. Thesupernatants collected for viral quantification using a standard plaqueassay using MA-104 cells as the indicator cells.

To perform the plaques assay, MA-104 cells were grown to confluence in24-well plates. The cells were washed with serum-free medium prior toinoculation of duplicate wells with serial 10-fold dilutions ofsupernatant sample. After 1 h incubation at 37° C., the samples wereaspirated and 1.0 mL of methyl cellulose overlay media was added to eachwell. After 6 days of culture, the cells were fixed and stained with0.06% crystal violet in 1% glutaraldehyde and viral plaques enumerated.The data was analyzed with Prism software with EC₅₀ defined as drugconcentration that reduced the viral load 50% from the viral control(VC). Table B1 provides a listing of compounds of Formula (I) that areactive against PIV-3 with an EC₅₀<20 μM.

TABLE B1 No.    2A   14A 15A 16A 17A 18A 19A 28A

Example 30 Human Metapneumovirus (hMPV) TCID₅₀ Assay

LLC-MK2 cells were grown in 24-well plates to a confluency of 90% in thepresence of minimal essential medium (MEM) supplemented with 10% fetalbovine serum and antibiotics (C-EMEM). The cells were then washed twicewith non-complete minimal essential medium (NC-EMEM). Test articles weredissolved in DMSO to a stock concentration of 10 mM.

An aliquot of 0.5 mL of the test article at various concentrations wasthen inoculated in triplicate wells and incubated for 60 mins at 37° C.with 5% CO₂ for the diffusion of test article into LLC-MK2 cells. Afterthe incubation period, a stock of human metapneumovirus was thawed anddiluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. Analiquot of 0.1 mL was then inoculated into all the wells except for thenegative and test article toxicity control wells. Upon infection, theplates were incubated for 7 days at 37° C. at 5% CO₂. After incubation,the plates were examined under microscopy to record cytotoxicity. Thesupernatants collected for viral quantification using a standard TCID₅₀assay using LLC-MK2 cells as the indicator cells. The data was analyzedwith Prism software with EC₅₀ defined as drug concentration that reducedthe viral load 50% from the viral control (VC). Table C1 provides alisting of compounds of Formula (I) that are active against humanmetapneumovirus, with an EC₅₀<20 μM.

TABLE C1 No. No. No. No. 2A 13A 16A 19A 7A 14A 17A 28A 8A 15A 18A

Although the foregoing has been described in some detail by way ofillustrations and examples for purposes of clarity and understanding, itwill be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure, but rather to also cover allmodification and alternatives coming with the true scope and spirit ofthe invention.

1. A compound of Formula (I), or a pharmaceutically acceptable saltthereof,

wherein: B^(1A) is an optionally substituted heterocyclic base or anoptionally substituted heterocyclic base with a protected amino group;R^(A) is hydrogen or deuterium; R^(1A) is selected from the groupconsisting of hydrogen, an optionally substituted acyl, an optionallysubstituted O-linked amino acid,

R^(a1) and R^(a2) are independently hydrogen or deuterium; R^(2A) is aC₁₋₆ azidoalkyl or a C₁₋₆ aminoalkyl; R^(3A) is selected from the groupconsisting of OH, —OC(═O)R″^(A) and an optionally substituted O-linkedamino acid; R^(4A) is halogen; R^(5A) is hydrogen or halogen; R^(6A),R^(7A) and R^(8A) are independently selected from the group consistingof absent, hydrogen, an optionally substituted C₁₋₂₄ alkyl, anoptionally substituted C₃₋₂₄ alkenyl, an optionally substituted C₃₋₂₄alkynyl, an optionally substituted C₃₋₆ cycloalkyl, an optionallysubstituted C₃₋₆ cycloalkenyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aryl(C₁₋₆alkyl), an optionally substituted *—(CR^(15A)R^(16A))_(p)—O—C₁₋₂₄ alkyl,an optionally substituted *—(CR^(17A)R^(18A))_(p)—O—C₁₋₂₄ alkenyl,

or R^(6A) is

and R^(7A) is absent or hydrogen; or R^(6A) and R^(7A) are takentogether to form a moiety selected from the group consisting of anoptionally substituted

and an optionally substituted

wherein the oxygens connected to R^(6A) and R^(7A), the phosphorus andthe moiety form a six-membered to ten-membered ring system; R^(9A) isindependently selected from the group consisting of an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted C₂₋₂₄ alkenyl, anoptionally substituted C₂₋₂₄ alkynyl, an optionally substituted C₃₋₆cycloalkyl, an optionally substituted C₃₋₆ cycloalkenyl,NR^(30A)R^(31A), an optionally substituted N-linked amino acid and anoptionally substituted N-linked amino acid ester derivative; R^(10A) andR^(11A) are independently an optionally substituted N-linked amino acidor an optionally substituted N-linked amino acid ester derivative;R^(12A), R^(13A) and R^(14A) are independently absent or hydrogen; eachR^(15A), each R^(16A), each R^(17A) and each R^(18A) are independentlyhydrogen, an optionally substituted C₁₋₂₄ alkyl or alkoxy; R^(19A),R^(20A), R^(22A) and R^(23A) are independently selected from the groupconsisting of hydrogen, an optionally substituted C₁₋₂₄ alkyl and anoptionally substituted aryl; R^(21A) and R^(24A) are independentlyselected from the group consisting of hydrogen, an optionallysubstituted C₁₋₂₄ alkyl, an optionally substituted aryl, an optionallysubstituted —O—C₁₋₂₄ alkyl, an optionally substituted —O-aryl anoptionally substituted —O-heteroaryl, an optionally substituted—O-monocyclic heterocyclyl and

R^(25A) and R^(29A) are independently selected from the group consistingof hydrogen, an optionally substituted C₁₋₂₄ alkyl and an optionallysubstituted aryl; R^(26A) and R^(27A) are independently —C≡N or anoptionally substituted substituent selected from the group consisting ofC₂₋₈ organylcarbonyl, C₂₋₈ alkoxycarbonyl and C₂₋₈ organylaminocarbonyl;R^(28A) is selected from the group consisting of hydrogen, an optionallysubstituted C₁₋₂₄-alkyl, an optionally substituted C₂₋₂₄ alkenyl, anoptionally substituted C₂₋₂₄ alkynyl, an optionally substituted C₃₋₆cycloalkyl and an optionally substituted C₃₋₆ cycloalkenyl; R^(30A) andR^(31A) are independently selected from the group consisting ofhydrogen, an optionally substituted C₁₋₂₄-alkyl, an optionallysubstituted C₂₋₂₄ alkenyl, an optionally substituted C₂₋₂₄ alkynyl, anoptionally substituted C₃₋₆ cycloalkyl and an optionally substitutedC₃₋₆ cycloalkenyl; R″^(A) is an optionally substituted C₁₋₂₄-alkyl; mand t are independently 0 or 1; p and q are independently selected fromthe group consisting of 1, 2 and 3; r is 1 or 2; s is 0, 1, 2 or 3; u is1 or 2; and Z^(1A), Z^(2A), Z^(3A) and Z^(4A) are independently O or S.2. The compound of claim 1, wherein R^(2A) is azidomethyl. 3.-66.(canceled)
 67. A pharmaceutical composition comprising an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, diluent, excipient,or combination thereof.
 68. A method for ameliorating or treating aparamyxovirus viral infection comprising administering to a subjectidentified as suffering from the paramyxovirus viral infection aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 69. A method for inhibiting replication of aparamyxovirus comprising contacting a cell infected with theparamyxovirus with an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 70. A method for amelioratingor treating a paramyxovirus viral infection comprising contacting a cellinfected with the paramyxovirus in a subject identified as sufferingfrom the viral infection with an effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 71. A method forameliorating or treating a paramyxovirus viral infection in combinationwith one or more agents comprising administering to or contacting a cellin a subject identified as suffering from the paramyxovirus viralinfection with an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 72. The method of claim 69,wherein the paramyxovirus viral infection is a human respiratorysyncytial virus infection.
 73. (canceled)
 74. The method of claim 69,wherein the paramyxovirus viral infection is a human parainfluenza virusinfection.
 75. The method of claim 74, wherein human parainfluenza virusinfection is a human parainfluenza virus 3 infection.
 76. The method ofclaim 69, wherein the paramyxovirus viral infection is a humanmetapneumovirus infection.